RARγ在PI3K/AKT和NF-κB信号交互通路中的作用
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摘要
视黄醇(retinoids)是天然的或人工合成的维生素A衍生物,在细胞的生长、分化以及凋亡中发挥着重要的作用。许多视黄醇类似物已经被开发成新的抗癌药物,并在临床上广泛应用于癌症的治疗。
视黄醇的生物学作用由视黄酸受体(Retinoic acid receptor,RAR)和视黄醇X受体(Retinoid X receptor,RXR)两类核受体所介导,这两类受体分别由α、β和γ三种不同的基因所编码,这些基因在进化上高度保守,但它们在胚胎发育调控过程中以及成年组织中的表达分布却不尽相同,说明不同受体具有各自独特的功能。
在本研究中,我们发现RARγ在不同的细胞和不同组织的表达水平有较大的差异,在肝癌组织中,我们发现该基因普遍高表达,在肝癌细胞HepG2的体外实验中,我们发现RARγ可以与p85α相互作用,从而激活PI3K/AKT信号通路,诱导IκBα磷酸化和p65向核内转位,激活NF-κB转录功能,并最终诱导AFP蛋白的表达。结果表明,RARγ在肝癌中的表达有可能介导炎症发生和促进癌细胞增殖,提示了RARγ有可能成为开发抗肝癌药物的一个有效的分子靶点。针对这样的分子机制,我们从天然产物中筛选到了一种黄酮类化合物——刺槐黄素,发现它能够通过诱导RARγ的降解来抑制AKT的磷酸化及肝癌细胞的生长。
Retinoids,a group of natural or synthetic vitamin A derivatives,play an important role in the regulation of cell proliferation,differentiation and apoptosis. Some of these compounds have been developed as effective anticancer drugs.
The biological actions of retinoids are primarily mediated through two classes of nuclear receptors,retinoic acid receptors(RARs) and retinoid X receptors(RXRs). Both RAR and RXR are encoded by three distinct genes,α,β,andγ,which are highly conserved amongst species and spatiotemporally expressed in developing embryos and adult tissues.Their distinct distributions suggest that individual isotypes may have unique and specific function.
In this study,we show that the expression level of RARγvaries among different tissues and that it is frequently overexpressed in liver tumors.Using in vitro cell culture system,we find that RARγupon binding to its ligand all-trans-retinoic acid (ATRA) interacts with the p85αregulatory subunit of the phosphoinositide 3-kinase (PI3K),leading to activation of PI3K and its downstream target AKT.The activation of PI3K/AKT signaling is accompanied with phosphorylation and degradation of inhibitor ofκBα(IκBα),which then stimulates nuclear translocation of p65/RelA and and NF-κB transcriptional activity.Based on our mechanistic studies,we have also screened a natural products library for antagonizing the RARγ-mediated NF-κB pathway and successfully identified a flavonoid derivative Acacetin that can induce RARγdegradation and inhibition of RARγ-mediated activation of PI3K/AKT/NF-κB signaling.Together,our results demonstrate that RARγfunctions to induce inflammation of liver cancer cells and their growth by nongenomically activating the PI3K/AKT/NF-κB pathway,suggesting that it may represents an attractive molecular target for developing anti-liver cancer agents.Our results also suggest that Acacetin is a promising lead for developing new agents for treating liver cancer.
视黄醇的生物学作用由视黄酸受体(Retinoic acid receptor,RAR)和视黄醇X受体(Retinoid X receptor,RXR)两类核受体所介导,这两类受体分别由α、β和γ三种不同的基因所编码,这些基因在进化上高度保守,但它们在胚胎发育调控过程中以及成年组织中的表达分布却不尽相同,说明不同受体具有各自独特的功能。
在本研究中,我们发现RARγ在不同的细胞和不同组织的表达水平有较大的差异,在肝癌组织中,我们发现该基因普遍高表达,在肝癌细胞HepG2的体外实验中,我们发现RARγ可以与p85α相互作用,从而激活PI3K/AKT信号通路,诱导IκBα磷酸化和p65向核内转位,激活NF-κB转录功能,并最终诱导AFP蛋白的表达。结果表明,RARγ在肝癌中的表达有可能介导炎症发生和促进癌细胞增殖,提示了RARγ有可能成为开发抗肝癌药物的一个有效的分子靶点。针对这样的分子机制,我们从天然产物中筛选到了一种黄酮类化合物——刺槐黄素,发现它能够通过诱导RARγ的降解来抑制AKT的磷酸化及肝癌细胞的生长。
Retinoids,a group of natural or synthetic vitamin A derivatives,play an important role in the regulation of cell proliferation,differentiation and apoptosis. Some of these compounds have been developed as effective anticancer drugs.
The biological actions of retinoids are primarily mediated through two classes of nuclear receptors,retinoic acid receptors(RARs) and retinoid X receptors(RXRs). Both RAR and RXR are encoded by three distinct genes,α,β,andγ,which are highly conserved amongst species and spatiotemporally expressed in developing embryos and adult tissues.Their distinct distributions suggest that individual isotypes may have unique and specific function.
In this study,we show that the expression level of RARγvaries among different tissues and that it is frequently overexpressed in liver tumors.Using in vitro cell culture system,we find that RARγupon binding to its ligand all-trans-retinoic acid (ATRA) interacts with the p85αregulatory subunit of the phosphoinositide 3-kinase (PI3K),leading to activation of PI3K and its downstream target AKT.The activation of PI3K/AKT signaling is accompanied with phosphorylation and degradation of inhibitor ofκBα(IκBα),which then stimulates nuclear translocation of p65/RelA and and NF-κB transcriptional activity.Based on our mechanistic studies,we have also screened a natural products library for antagonizing the RARγ-mediated NF-κB pathway and successfully identified a flavonoid derivative Acacetin that can induce RARγdegradation and inhibition of RARγ-mediated activation of PI3K/AKT/NF-κB signaling.Together,our results demonstrate that RARγfunctions to induce inflammation of liver cancer cells and their growth by nongenomically activating the PI3K/AKT/NF-κB pathway,suggesting that it may represents an attractive molecular target for developing anti-liver cancer agents.Our results also suggest that Acacetin is a promising lead for developing new agents for treating liver cancer.
引文
[1]Sporn MB.Dunlop NM,.et al.Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs(retinoids).[J].Fed.Proc.1976,(35):1332-1338.
[2]Lotan R.Effects of vitamin A and its analogs(retinoids) on normal and neoplastic cells.[J].Biochim.Biophys.Acta.1980,(605):33-91.
[3]Lotan R.Retinoids and apoptosis:implications for cancer chemoprevention and therapy.[J].J.Natl.Cancer Inst.1995(87):1655-1657.
[4]Nagy L,Thomazy VA.et al.Retinoid-induced apoptosis in normal and neoplastic tissues.[J].Cell Death.Differ.1998,5(1):11-19.
[5]De Luca LM Retinoids and their receptors in differentiation,embryogenesis,and neoplasia.[J].FASEB J,1991.5(14):2924-2933.
[6]Gudas L J,Sporn MB,et al.Cellular biology and biochemistry of the retinoids[M].New York:Raven Press In:Sporn MB.Roberts AB.Goodman DS.editors.The retinoids.1994:443-520.
[7]ManuelMark.NorbertB.et al.Function ofretinoid of retinoid nuclear receptors:Lessons from Genetic and Pharmacological Dissections of the Retinoic Acid Signaling Pathway During Mouse Embryogenesis.[J].Annu.Rev.Pharmacol.Toxicol.2006.(46):451-480.
[8]Louise E.Purton.Sebastian Dworkin.et al.RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.[J].JEM..2006,(203):1283-1293.
[9]Chambon P.A decade of molecular biology of retinoic acid receptors[J].FASEB J.1996.10(9):940-954.
[10]Mangelsdorf DJ,Umesono K.et al.The retinoid receptors[M].New York:Raven Press.In:Spore MB,Roberts AB.Goodman DS.editors.The retinoids.1994:319-350.
[11]Zechel C.Shen XQ.et al.Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements[J].EMBO J.1994.(13):1414-1424.
[12]Zechel C,Shen XQ,et al.Yhe dimerization interfaces formed between the DNA binding domains of RXR,RAR and TR determine the binding specificity and polarity of the full-length receptors to direct repeats[J].EMBO J.1994,13(6):1425-1433.
[13]吴乔,苏文金.视黄醇受体结构及其一些生物学特性[J].细胞生物学杂志.1999.21:62-67
[14]Lee MS,Kliewer SA,et al.Structure of the retinoid X receptor alpha DNA binding domain:a helix required for homodimeric DNA binding[J].Science.1993.260(5111):1117-1121.
[15]Bourguet W.RuffM,et al.Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha.[J].Nature.1995,(375):377-382.
[16]Renaud JP,Rochel N,et al.Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid.[J].Nature.1995,(378):681-689.
[17]Bastien J,Rochette-Egly C.Nuclear retinoid receptors and the transcription ofretinoid-target genes.[J].Gene 2004,(328):1-16.
[18] Metivier R. Stark A. et al.A dynamic structural model for estrogen receptor-alpha activation by ligands. emphasizing the role of interactions between distant A and E domains. [J].Mol.Cell 2002.(10): 1019-1032.
[19] Montano MM, Muller V, et al. The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. [J].Mol. Endocrinol.1995,(9): 814-82.
[20] Yuichi Hashimoto.Retinobenzoic acids and nuclear retinoic acid receptors. [J].Cell structure and function. 1991.16:113-123.
[21] Petkovich, M., et al. A human retinoic acid receptor which belongs to the family of nuclear receptors[J]. Nature. 1987.330:444-450.
[22] Giguere. V., Ong. E. S.. et al. Identification of a receptor for the morphogen retinoic acid[J]. Nature. 1987.330:624-629.
[23] Mangelsdorf, D. J.. Ong. E. S.. et al.Nuclear receptor that identifies a novel retinoic acid response pathway[J]. Nature. 1990. 345.224-229.
[24] Eager. N. S.. Rowe. et al.A member of the chicken RXR family of nuclear receptors activates transcription in response to retinoic acid[J]. FEBS Lett. 1991.292:103-106.
[25] Leid,M..Kastner.P..et al. cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently[J].Cell.1992.68:377-395.
[26] Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors [J]. Cell .1995. 83 (6): 841-850.
[27] Leid M. Kastner P. et al. Multiplicity generates diversity in the retinoic acid signalling pathways [J]. Trends Biochem. Sci. 1992. 17(10): 427-433.
[28] Kliewer SA. Umesono K. et al.Retinoid X receptor interacts with nuclear receptors in retinoic acid. thyroid hormone and vitamin D3 signalling [J]. Nature 1992. 355 (6359): 446-449.
[29] Bugge TH, Pohl J. et al. RXR alpha. a promiscuous partner of retinoic acid and thyroid hormone receptors [J]. EMBOJ. 1992. 11 (4): 1409-1418.
[30] Mangelsdorf DJ, Umesono K. et al.The retinoid receptors [M]. New York: Raven Press. In: Sporn MB. Roberts AB. Goodman DS. editors. The retinoids. 1994:319-350.
[31] Durand B, Saunders M. et al.All-trans and 9-cis retinoic acid induction of CRABPI1 transcription is mediated by RAR-RXR heterodimers bound to DRI and DR2 repeated motifs [J]. Cell 1992. 71 (1): 73-85.
[32] Wehling M .Specific, nongenomic actions of steroid hormones[J]. Annu Rev Physiol .1997 .59:365-393
[33] Valverde MA, Parker MG .Classical and novel steroid actions: a unified but complex view. Trends Biochem[J].Sci 2002 .27:172-173.
[34] Losel R, Wehling M . Nongenomic actions of steroid hormones[J]. Nat Rev Mol Cell Biol.2003. 4:46-56.
[35] Simoncini T, Genazzani AR .Non-genomic actions of sex steroid hormones[J]. Eur J Endocrinol.2003 . 148:281-292.
[36] Masia, S., S. Alvarez, et al. Rapid. nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor[J]. Mol Endocrinol 2007.21(10): 2391-402.
[37] Hughes, P. J., Y. Zhao, et al. Retinoid-mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARalpha and RXR and involves the phosphoinositide 3-kinase and ERK-MAP kinase pathways[J].J Cell Biochem. 2006.97(2): 327-50.
[38] Sun SY. Lotan R. Retinoids and their receptors in cancer development and chemoprevention[J].Crit Rev. Oncol. Hematol. 2002, (41):41-55.
[39] Yarali. N.. B. Tavil. et al.Acute renal failure during ATRA treatment[J].Pediatr Hematol Oncol.2008.25(2): 115-8.
[40] Woo, K. T.. Y. K. Lau. et al.ATRA therapy restores normal renal function and renal reserve and prevents renal failure[J]. Ann Acad Med Singapore.2005. 34(1): 52-9.
[41] Pavithran. K., R. Arjun. et al. Scrotal ulceration during induction therapy of acute promyelocytic leukemia with ATRA[J].Am J Hematol.2004.75(4): 260-1.
[42] Paydas, S., S. Yavuz. et al. Vasculitis associated with all trans retinoic acid (ATRA) in a case with acute promyelocytic leukemia.Leuk Lymphoma.2003.44(3): 547-8.
[43] Dombret. H.. S. Geiger. et al. Changes in microrheology of acute promyelocytic leukemia cells during all-trans retinoic acid (ATRA)differentiation therapy: a mechanism for ATRA-induced hyperleukocytosis?[J]. Leukemia. 1995,9(9): 1473-7
[44] Mathieu. J. and F. Besancon.Arsenic trioxide represses NF-kappaB activation and increases apoptosis in ATRA-treated APL cells[J]._Ann N Y Acad Sci.2006.1090: 203-8.
[45] Datta. S. R.. A. Brunet. et al.Cellular survival: a play in three Akts[J].Genes Dev 1999.13(22): 2905-27.
[46] Vivanco, 1. and C. L. Sawyers. The phosphatidylinositol 3-Kinase AKT pathway in human cancer[J].Nat Rev Cancer .2002.2(7): 489-501.
[47] Di Cristofano. A., P. Kotsi. et al.Impaired Fas response and autoimmunity in Pten+/- mice[J]. Science. 1999,285(5436): 2122-5.
[48] Nicholson. K. M. and N. G. Anderson.The protein kinase B/Akt signalling pathway in human malignancy[J].Cell Signal.2002.14(5):381-95.
[49] Xu. Q.. S. E. Simpson, et al.Survival of acute myeloid leukemia cells requires PI3 kinase activation[J]. Blood .2003.102(3): 972-80.
[50] Kubota. Y, H. Ohnishi. et al.Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells: direct evidence of PI3K activation[J].Leukemia .2004). 18(8): 1438-40.
[51] Min. Y. H., J. I. Eom. et al.Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable[J].Leukemia.2003.17(5): 995-7.
[52] Cheng. J. Q., A. K. Godwin, et al. AKT2. a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases. is amplified in human ovarian carcinomas[J].Proc Natl Acad Sci U S A. 1992,89(19): 9267-71.
[53] Bellacosa. A., D. de Feo. et al.Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas[J]. Int J Cancer . 1995,64(4): 280-5.
[54] Cheng. J. Q.. B. Ruggeri. et al.Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA[J].Proc Natl Acad Sci U S A .1996.93(8): 3636-41.
[55] Ringel. M. D., N. Hayre. et al. Overexpression and overactivation of Akt in thyroid carcinoma[J].Cancer Res.2001.61(16): 6105-11.
[56] Yuan, Z. Q., M. Sun. et al. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer[J].Oncogene. 2000.19(19): 2324-30.
[57] Zhao, S., M. Konopleva. et al.Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias[J]. Leukemia.2004.18(2): 267-75.
[58] Tabellini, G. P. L. Tazzari. et al.Novel 2'-substituted, 3'-deoxy-phosphatidyl-myo-inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3-kinase/Akt pathway[J].Br J Haematol.2004,126(4): 574-82.
[59] Mills, G. B., Y. Lu. et al. Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo[J].Proc Natl Acad Sci U S A.2001.98(18): 10031-3.
[60] Voigt P., C. Brock, et al.Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase gamma[J]. J Biol Chem.2005. 280(6):5121-7.
[61] Cantley, L. C. The phosphoinositide 3-kinase pathway[J].Science.2002.296(5573): 1655-7.
[62] Vanhaesebroeck,B.. S. J. Leevers.et al.Synthesis and function of 3-phosphorylated inositol lipids[J].Annu Rev Biochem .2001,70: 535-602.
[63] Dowler, S., R. A. Currie, et al.Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities[J].Biochem J .2000.351(Pt 1): 19-31.
[64] Hirsch, E., V. L. Katanaev. et al.Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation[J]. Science.2000.287(5455): 1049-53.
[65] Staal. S. P..Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma[J]. Proc Natl Acad Sci U S A .1987.84(14): 5034-7.
[66] Datta, S. R., A. Brunet. et al.Cellular survival: a play in three Akts[J].Genes Dev. 1999.13(22): 2905-27.
[67] Brodbeck, D.. P. Cron. et al.A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain[J].J Biol Chem.1999.274(14): 9133-6.
[68] Altomare, D. A.. G. E. Lyons, et al.Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin[J].Oncogene.l998,16(18): 2407-11.
[69] Altomare, D. A.. K. Guo. et al.Cloning. chromosomal localization and expression analysis of the mouse Akt2 oncogene[J].Oncogene.l995, 11(6): 1055-60.
[70] Alessi, D. R., M. Andjelkovic, et al.Mechanism of activation of protein kinase B by insulin and IGF-1[J]. EMBO J.1996,15(23): 6541-51.
[71] Delcommenne,M.,C.Tan,et al.Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase[J].Proc Natl Acad Sci U S A .1998.95(19): 11211-6.
[72] Vanhaesebroeck, B. and M. D. Waterfield.Signaling by distinct classes of phosphoinositide 3-kinases[J]." Exp Cell Res. 1999. 253(1): 239-54.
[73] Lum, D. H., P. E. Kuwabara. et al.Direct protein-protein interaction between the intracellular domain of TRA-2 and the transcription factor TRA-1A modulates feminizing activity in C. EIegans[J].Genes Dev.2000,14(24):3153-65.
[74]Fruman,D.A.,L.E.Rameh.et al.Phosphoinositide binding domains:embracing 3-phosphate[J].Cell.1999,97(7):817-20.
[75]Cross,D.A.,D.R.Alessi.et al.Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B[J].Nature.1995,378(6559):785-9.
[76]Sekulic,A.,C.C.Hudson.et al.A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells[J].Cancer Res.2000,60(13):3504-13.
[77]Sen,R.and D.Baltimore.Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism[J].Cell.1986.47(6):921-8.
[78]史艳晖,卢圣栋.转录因子Nf-kappa B的研究现状及应用前景[J].中国生物工程杂志.2007,27(4):110-114.
[79]May,M.J.and S.Ghosh.IkappaB kinases:kinsmen with different crafts[J].Science.1999,284(5412):271-3.
[80]Elsharkawy.A.M.and D.A.Mann.Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis[J].Hepatology.2007.46(2):590-7.
[81]Lorraine I,Mckay.John A.Molecular control of innune/inflammatory response:Interactions between nuclear factor-kB and steroid receptor-signaling pathway[J].Endocrine Review.2004,435-459.
[82]Yamazaki,S.,T.Muta,et al.A novel IkappaB protein,IkappaB-zeta.induced by proinflammatory stimuli.negatively regulates nuclear factor-kappaB in the nuclei[J].J Biol Chem.2001,276(29):27657-62.
[83]Vermeulen,L.,G.De Wilde,et al.Regulation of the transcriptional activity of the nuclear factor-kappaB p65subunit[J].Biochem Pharmacol.2002,64(5-6):963-70.
[84]Viatour.P.,M.P.Merville,et al.Phosphorylation of NF-kappaB and IkappaB proteins:implications in cancer and inflammation[J].Trends Biochem Sci.2005,30(1):43-52.
[85]Garcia,M.G.,L.D.Alaniz.et al.PI3K/Akt inhibition modulates multidrug resistance and activates NF-kappaB in murine lymphoma cell lines[J].Leuk Res.2009,33(2):288-96.
[86]Kim,N.H.,S.Jeon,et al.Impaired PI3K/Akt activation-mediated NF-kappaB inactivation under elevated TNF-alpha is more vulnerable to apoptosis in vitiliginous keratinocytes[J].J Invest Dermatol.2007,127(11):2612-7.
[87]Qiu,L.,L.Zhang,et al.PI3K/Akt mediates expression of TNF-alpha mRNA and activation of NF-kappaB in calyculin A-treated primary osteoblasts[J].Oral Dis.2008,14(8):727-33.
[88]Romashkova,J.A.and S.S.Makarov.NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling[J].Nature.1999,401(6748):86-90.
[89]hong,C.,S.Yang,et al.Aberration in the expression of the retinoid receptor,RXRalpha in prostate cancer[J].Cancer Biol Ther.2003,2(2):179-84.
[90]Rajaii,F.,Z.T.Bitzer.et al.Expression of the dominant negative retinoid receptor,RAR403.alters telencephalic progenitor proliferation,survival,and cell fate specification[J].Dev Biol.2008,316(2):371-82.
[91]Hoegberg,P.,C.K.Schmidt,et al.Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms[J].Chem Biol Interact.2005,156(1):25-39.
[92] Richter, F., A. Joyce. et al.Immunohistochemical localization of the retinoic Acid receptors in human prostate[J].J Androl.2002.23(6): 830-8.
[93] Gyftopoulos K, Perimenis P. Sotiropoulou-Bonikou G, SakellaropoulosG. Varakis I. Barbalias GA. Immunohistochemical detection of retinoic acid receptor in prostate carcinoma: correlation with proliferative activity and tumor grade[J]. Int Urol Nephrol. 2000.32:263-269.
[94] Baron, S.. M. Manin. et al.Androgen receptor mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells[J]. J Biol Chem.2004. 279(15): 14579-86.
[95] Arce. F., O. Gatjens-Boniche. et al.Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2[J].Cancer Lett.2005. 229(2): 271-81.
[96] Mizejewski GJ, MacColl R. Alpha-fetoprotein growth inhibitory peptides: potential leads for cancer therapeutics[J]. Mol Cancer Ther .2003.2:1243-55.
[97] Vakharia D, Mizejewski GJ. Human alpha-fetoprotein peptides bind estrogen receptor and estradiol. and suppress breast cancer[J]. Breast Cancer Res Treat .2000.63:41-52.
[98] Muehlemann M, Miller KD. et al. Review of growth inhibitory peptide as a biotherapeutic agent for tumor growth, adhesion. and metastasis[J]. Cancer Metastasis Rev. 2005.24:441-67.
[99] Li MS, Li PF. et al. Alpha-fetoprotein stimulated the expression of some oncogenes in human hepatocellular carcinoma Bel 7402 cells[J]. World J Gastroenterol 2004.10:819-24.
[100] Gotoh M, Nakatani T. et al.Prediction of invasive activities in hepatocellular carcinomas with special reference to alpha-fetoprotein and desgamma-carboxyprothrombin[J]. Jpn J Clin Oncol 2003,33:522-6.
[101] Iida H, Honda M, et al.Ephrin-Al expression contributes to the malignant characteristics of alpha-fetoprotein producing hepatocellular carcinoma[J].Gut .2005.54:843-51.
[102] Ishigami S, Natsugoe S.et al.Biological aggressiveness of alpha-fetoprotein (AFP)-positive gastric cancer[J].Hepatogastroenterology.2006.53:338-41.
[103] Cavin, L. G., M. Venkatraman, et al. Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis[J] .Cancer Res.2004. 64(19): 7030-8.
[104] Pan, M. H., C. S. Lai, et al. Acacetin induces apoptosis in human gastric carcinoma cells accompanied by activation of caspase cascades and production of reactive oxygen species[J].J Agric Food Chem. 2005. 53(3): 620-30.
[105] Singh, R. P., P. Agrawal. et al.Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: structure-activity relationship with linarin and linarin acetate[J]. Carcinogenesis.2005, 26(4): 845-54.
[106] Shim, H. Y., J. H. Park, et al. Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation[J].Mol Cells.2007, 24(1): 95-104.
[107] Hsu, Y. L., P. L. Kuo, et al.Acacetin-induced cell cycle arrest and apoptosis in human non-small cell lung cancer A549 cells[J].Cancer Lett.2004. 212(1): 53-60.
[108] Zhang, L., R. Zhou, et al.Stress-induced change of mitochondria membrane potential regulated by genomic and non-genomic GR signaling: a possible mechanism for hippocampus atrophy in PTSD[J].Med Hypotheses.2006, 66(6): 1205-8.
[109] Safe, S. and K. Kim .Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways[J]. J Mol Endocrinol.2008.41(5): 263-75.
[110] Robinson-Rechavi. M.. H. Escriva Garcia, et al.The nuclear receptor superfami]y[J]. J Cell Sci .2003.116(Pt 4): 585-6.
[11] Valledor. A. F. and M. Ricote.Nuclear receptor signaling in macrophages[J]. Biochem Pharmacol.2004, 67(2):201-12.
[112] Dees. E. C. and M. J. Kennedy.Recent advances in systemic therapy for breast cancer[J].Curr Opin Oncol. 1998. 10(6): 517-22.
[113] Olefsky. J. M. and A. R. Saltiel.PPAR gamma and the treatment of insulin resistance[J]. Trends Endocrinol Metab.2000.11(9): 362-8.
[114] Dyer. M. J. PML/RAR alpha + ATRA = CR. A comment on acute promyelocytic leukaemia: molecular pathology and treatment[J]._Eur J Cancer. 1994. 30A(5): 573-4.
[115] Sun. T.. H. Takatsuki. et al.Detection of minimal residual disease in a patient with acute promyelocytic leukemia by RT-PCR: necessity of chemotherapy following ATRA therapy[J].Fukuoka Igaku Zasshi.1994. 85(2): 52-6.
[116] Han YH, Zhou H. et al. A unique cytoplasmic localization of RARgamma and its regulations[J].J Biol Chem. J Biol Chem. 2009 May 5. [Epub ahead of print]
[117] Benbrook. D.. E. Lernhardt. et al.A new retinoic acid receptor identified from a hepatocellular carcinoma[J].Nature .1988)333(6174): 669-72.
[118] Keller. H., C. Dreyer. et al .Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers[J]. Proc Natl Acad Sci U S A.. 1993. 90(6): 2160-4.
[119] Zhang. X.-K... J. M. Lehmann, B .et al. Ho-modimer formation of retinoid X receptor induced by 9-cis retinoic acid[J]. Nature (London) .1992.358:587-591.
[120] Lehmann. J. M.. X. K. Zhang. et al.Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching[J]. Mol Cell Biol. 1993.13(12): 7698-707.
[121] Lin. B., S. K. Kolluri. et al.Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3[J]. Cell. 2004.116(4): 527-40.
[2]Lotan R.Effects of vitamin A and its analogs(retinoids) on normal and neoplastic cells.[J].Biochim.Biophys.Acta.1980,(605):33-91.
[3]Lotan R.Retinoids and apoptosis:implications for cancer chemoprevention and therapy.[J].J.Natl.Cancer Inst.1995(87):1655-1657.
[4]Nagy L,Thomazy VA.et al.Retinoid-induced apoptosis in normal and neoplastic tissues.[J].Cell Death.Differ.1998,5(1):11-19.
[5]De Luca LM Retinoids and their receptors in differentiation,embryogenesis,and neoplasia.[J].FASEB J,1991.5(14):2924-2933.
[6]Gudas L J,Sporn MB,et al.Cellular biology and biochemistry of the retinoids[M].New York:Raven Press In:Sporn MB.Roberts AB.Goodman DS.editors.The retinoids.1994:443-520.
[7]ManuelMark.NorbertB.et al.Function ofretinoid of retinoid nuclear receptors:Lessons from Genetic and Pharmacological Dissections of the Retinoic Acid Signaling Pathway During Mouse Embryogenesis.[J].Annu.Rev.Pharmacol.Toxicol.2006.(46):451-480.
[8]Louise E.Purton.Sebastian Dworkin.et al.RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.[J].JEM..2006,(203):1283-1293.
[9]Chambon P.A decade of molecular biology of retinoic acid receptors[J].FASEB J.1996.10(9):940-954.
[10]Mangelsdorf DJ,Umesono K.et al.The retinoid receptors[M].New York:Raven Press.In:Spore MB,Roberts AB.Goodman DS.editors.The retinoids.1994:319-350.
[11]Zechel C.Shen XQ.et al.Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements[J].EMBO J.1994.(13):1414-1424.
[12]Zechel C,Shen XQ,et al.Yhe dimerization interfaces formed between the DNA binding domains of RXR,RAR and TR determine the binding specificity and polarity of the full-length receptors to direct repeats[J].EMBO J.1994,13(6):1425-1433.
[13]吴乔,苏文金.视黄醇受体结构及其一些生物学特性[J].细胞生物学杂志.1999.21:62-67
[14]Lee MS,Kliewer SA,et al.Structure of the retinoid X receptor alpha DNA binding domain:a helix required for homodimeric DNA binding[J].Science.1993.260(5111):1117-1121.
[15]Bourguet W.RuffM,et al.Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha.[J].Nature.1995,(375):377-382.
[16]Renaud JP,Rochel N,et al.Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid.[J].Nature.1995,(378):681-689.
[17]Bastien J,Rochette-Egly C.Nuclear retinoid receptors and the transcription ofretinoid-target genes.[J].Gene 2004,(328):1-16.
[18] Metivier R. Stark A. et al.A dynamic structural model for estrogen receptor-alpha activation by ligands. emphasizing the role of interactions between distant A and E domains. [J].Mol.Cell 2002.(10): 1019-1032.
[19] Montano MM, Muller V, et al. The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. [J].Mol. Endocrinol.1995,(9): 814-82.
[20] Yuichi Hashimoto.Retinobenzoic acids and nuclear retinoic acid receptors. [J].Cell structure and function. 1991.16:113-123.
[21] Petkovich, M., et al. A human retinoic acid receptor which belongs to the family of nuclear receptors[J]. Nature. 1987.330:444-450.
[22] Giguere. V., Ong. E. S.. et al. Identification of a receptor for the morphogen retinoic acid[J]. Nature. 1987.330:624-629.
[23] Mangelsdorf, D. J.. Ong. E. S.. et al.Nuclear receptor that identifies a novel retinoic acid response pathway[J]. Nature. 1990. 345.224-229.
[24] Eager. N. S.. Rowe. et al.A member of the chicken RXR family of nuclear receptors activates transcription in response to retinoic acid[J]. FEBS Lett. 1991.292:103-106.
[25] Leid,M..Kastner.P..et al. cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently[J].Cell.1992.68:377-395.
[26] Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors [J]. Cell .1995. 83 (6): 841-850.
[27] Leid M. Kastner P. et al. Multiplicity generates diversity in the retinoic acid signalling pathways [J]. Trends Biochem. Sci. 1992. 17(10): 427-433.
[28] Kliewer SA. Umesono K. et al.Retinoid X receptor interacts with nuclear receptors in retinoic acid. thyroid hormone and vitamin D3 signalling [J]. Nature 1992. 355 (6359): 446-449.
[29] Bugge TH, Pohl J. et al. RXR alpha. a promiscuous partner of retinoic acid and thyroid hormone receptors [J]. EMBOJ. 1992. 11 (4): 1409-1418.
[30] Mangelsdorf DJ, Umesono K. et al.The retinoid receptors [M]. New York: Raven Press. In: Sporn MB. Roberts AB. Goodman DS. editors. The retinoids. 1994:319-350.
[31] Durand B, Saunders M. et al.All-trans and 9-cis retinoic acid induction of CRABPI1 transcription is mediated by RAR-RXR heterodimers bound to DRI and DR2 repeated motifs [J]. Cell 1992. 71 (1): 73-85.
[32] Wehling M .Specific, nongenomic actions of steroid hormones[J]. Annu Rev Physiol .1997 .59:365-393
[33] Valverde MA, Parker MG .Classical and novel steroid actions: a unified but complex view. Trends Biochem[J].Sci 2002 .27:172-173.
[34] Losel R, Wehling M . Nongenomic actions of steroid hormones[J]. Nat Rev Mol Cell Biol.2003. 4:46-56.
[35] Simoncini T, Genazzani AR .Non-genomic actions of sex steroid hormones[J]. Eur J Endocrinol.2003 . 148:281-292.
[36] Masia, S., S. Alvarez, et al. Rapid. nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor[J]. Mol Endocrinol 2007.21(10): 2391-402.
[37] Hughes, P. J., Y. Zhao, et al. Retinoid-mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARalpha and RXR and involves the phosphoinositide 3-kinase and ERK-MAP kinase pathways[J].J Cell Biochem. 2006.97(2): 327-50.
[38] Sun SY. Lotan R. Retinoids and their receptors in cancer development and chemoprevention[J].Crit Rev. Oncol. Hematol. 2002, (41):41-55.
[39] Yarali. N.. B. Tavil. et al.Acute renal failure during ATRA treatment[J].Pediatr Hematol Oncol.2008.25(2): 115-8.
[40] Woo, K. T.. Y. K. Lau. et al.ATRA therapy restores normal renal function and renal reserve and prevents renal failure[J]. Ann Acad Med Singapore.2005. 34(1): 52-9.
[41] Pavithran. K., R. Arjun. et al. Scrotal ulceration during induction therapy of acute promyelocytic leukemia with ATRA[J].Am J Hematol.2004.75(4): 260-1.
[42] Paydas, S., S. Yavuz. et al. Vasculitis associated with all trans retinoic acid (ATRA) in a case with acute promyelocytic leukemia.Leuk Lymphoma.2003.44(3): 547-8.
[43] Dombret. H.. S. Geiger. et al. Changes in microrheology of acute promyelocytic leukemia cells during all-trans retinoic acid (ATRA)differentiation therapy: a mechanism for ATRA-induced hyperleukocytosis?[J]. Leukemia. 1995,9(9): 1473-7
[44] Mathieu. J. and F. Besancon.Arsenic trioxide represses NF-kappaB activation and increases apoptosis in ATRA-treated APL cells[J]._Ann N Y Acad Sci.2006.1090: 203-8.
[45] Datta. S. R.. A. Brunet. et al.Cellular survival: a play in three Akts[J].Genes Dev 1999.13(22): 2905-27.
[46] Vivanco, 1. and C. L. Sawyers. The phosphatidylinositol 3-Kinase AKT pathway in human cancer[J].Nat Rev Cancer .2002.2(7): 489-501.
[47] Di Cristofano. A., P. Kotsi. et al.Impaired Fas response and autoimmunity in Pten+/- mice[J]. Science. 1999,285(5436): 2122-5.
[48] Nicholson. K. M. and N. G. Anderson.The protein kinase B/Akt signalling pathway in human malignancy[J].Cell Signal.2002.14(5):381-95.
[49] Xu. Q.. S. E. Simpson, et al.Survival of acute myeloid leukemia cells requires PI3 kinase activation[J]. Blood .2003.102(3): 972-80.
[50] Kubota. Y, H. Ohnishi. et al.Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells: direct evidence of PI3K activation[J].Leukemia .2004). 18(8): 1438-40.
[51] Min. Y. H., J. I. Eom. et al.Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable[J].Leukemia.2003.17(5): 995-7.
[52] Cheng. J. Q., A. K. Godwin, et al. AKT2. a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases. is amplified in human ovarian carcinomas[J].Proc Natl Acad Sci U S A. 1992,89(19): 9267-71.
[53] Bellacosa. A., D. de Feo. et al.Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas[J]. Int J Cancer . 1995,64(4): 280-5.
[54] Cheng. J. Q.. B. Ruggeri. et al.Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA[J].Proc Natl Acad Sci U S A .1996.93(8): 3636-41.
[55] Ringel. M. D., N. Hayre. et al. Overexpression and overactivation of Akt in thyroid carcinoma[J].Cancer Res.2001.61(16): 6105-11.
[56] Yuan, Z. Q., M. Sun. et al. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer[J].Oncogene. 2000.19(19): 2324-30.
[57] Zhao, S., M. Konopleva. et al.Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias[J]. Leukemia.2004.18(2): 267-75.
[58] Tabellini, G. P. L. Tazzari. et al.Novel 2'-substituted, 3'-deoxy-phosphatidyl-myo-inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3-kinase/Akt pathway[J].Br J Haematol.2004,126(4): 574-82.
[59] Mills, G. B., Y. Lu. et al. Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo[J].Proc Natl Acad Sci U S A.2001.98(18): 10031-3.
[60] Voigt P., C. Brock, et al.Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase gamma[J]. J Biol Chem.2005. 280(6):5121-7.
[61] Cantley, L. C. The phosphoinositide 3-kinase pathway[J].Science.2002.296(5573): 1655-7.
[62] Vanhaesebroeck,B.. S. J. Leevers.et al.Synthesis and function of 3-phosphorylated inositol lipids[J].Annu Rev Biochem .2001,70: 535-602.
[63] Dowler, S., R. A. Currie, et al.Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities[J].Biochem J .2000.351(Pt 1): 19-31.
[64] Hirsch, E., V. L. Katanaev. et al.Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation[J]. Science.2000.287(5455): 1049-53.
[65] Staal. S. P..Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma[J]. Proc Natl Acad Sci U S A .1987.84(14): 5034-7.
[66] Datta, S. R., A. Brunet. et al.Cellular survival: a play in three Akts[J].Genes Dev. 1999.13(22): 2905-27.
[67] Brodbeck, D.. P. Cron. et al.A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain[J].J Biol Chem.1999.274(14): 9133-6.
[68] Altomare, D. A.. G. E. Lyons, et al.Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin[J].Oncogene.l998,16(18): 2407-11.
[69] Altomare, D. A.. K. Guo. et al.Cloning. chromosomal localization and expression analysis of the mouse Akt2 oncogene[J].Oncogene.l995, 11(6): 1055-60.
[70] Alessi, D. R., M. Andjelkovic, et al.Mechanism of activation of protein kinase B by insulin and IGF-1[J]. EMBO J.1996,15(23): 6541-51.
[71] Delcommenne,M.,C.Tan,et al.Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase[J].Proc Natl Acad Sci U S A .1998.95(19): 11211-6.
[72] Vanhaesebroeck, B. and M. D. Waterfield.Signaling by distinct classes of phosphoinositide 3-kinases[J]." Exp Cell Res. 1999. 253(1): 239-54.
[73] Lum, D. H., P. E. Kuwabara. et al.Direct protein-protein interaction between the intracellular domain of TRA-2 and the transcription factor TRA-1A modulates feminizing activity in C. EIegans[J].Genes Dev.2000,14(24):3153-65.
[74]Fruman,D.A.,L.E.Rameh.et al.Phosphoinositide binding domains:embracing 3-phosphate[J].Cell.1999,97(7):817-20.
[75]Cross,D.A.,D.R.Alessi.et al.Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B[J].Nature.1995,378(6559):785-9.
[76]Sekulic,A.,C.C.Hudson.et al.A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells[J].Cancer Res.2000,60(13):3504-13.
[77]Sen,R.and D.Baltimore.Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism[J].Cell.1986.47(6):921-8.
[78]史艳晖,卢圣栋.转录因子Nf-kappa B的研究现状及应用前景[J].中国生物工程杂志.2007,27(4):110-114.
[79]May,M.J.and S.Ghosh.IkappaB kinases:kinsmen with different crafts[J].Science.1999,284(5412):271-3.
[80]Elsharkawy.A.M.and D.A.Mann.Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis[J].Hepatology.2007.46(2):590-7.
[81]Lorraine I,Mckay.John A.Molecular control of innune/inflammatory response:Interactions between nuclear factor-kB and steroid receptor-signaling pathway[J].Endocrine Review.2004,435-459.
[82]Yamazaki,S.,T.Muta,et al.A novel IkappaB protein,IkappaB-zeta.induced by proinflammatory stimuli.negatively regulates nuclear factor-kappaB in the nuclei[J].J Biol Chem.2001,276(29):27657-62.
[83]Vermeulen,L.,G.De Wilde,et al.Regulation of the transcriptional activity of the nuclear factor-kappaB p65subunit[J].Biochem Pharmacol.2002,64(5-6):963-70.
[84]Viatour.P.,M.P.Merville,et al.Phosphorylation of NF-kappaB and IkappaB proteins:implications in cancer and inflammation[J].Trends Biochem Sci.2005,30(1):43-52.
[85]Garcia,M.G.,L.D.Alaniz.et al.PI3K/Akt inhibition modulates multidrug resistance and activates NF-kappaB in murine lymphoma cell lines[J].Leuk Res.2009,33(2):288-96.
[86]Kim,N.H.,S.Jeon,et al.Impaired PI3K/Akt activation-mediated NF-kappaB inactivation under elevated TNF-alpha is more vulnerable to apoptosis in vitiliginous keratinocytes[J].J Invest Dermatol.2007,127(11):2612-7.
[87]Qiu,L.,L.Zhang,et al.PI3K/Akt mediates expression of TNF-alpha mRNA and activation of NF-kappaB in calyculin A-treated primary osteoblasts[J].Oral Dis.2008,14(8):727-33.
[88]Romashkova,J.A.and S.S.Makarov.NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling[J].Nature.1999,401(6748):86-90.
[89]hong,C.,S.Yang,et al.Aberration in the expression of the retinoid receptor,RXRalpha in prostate cancer[J].Cancer Biol Ther.2003,2(2):179-84.
[90]Rajaii,F.,Z.T.Bitzer.et al.Expression of the dominant negative retinoid receptor,RAR403.alters telencephalic progenitor proliferation,survival,and cell fate specification[J].Dev Biol.2008,316(2):371-82.
[91]Hoegberg,P.,C.K.Schmidt,et al.Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms[J].Chem Biol Interact.2005,156(1):25-39.
[92] Richter, F., A. Joyce. et al.Immunohistochemical localization of the retinoic Acid receptors in human prostate[J].J Androl.2002.23(6): 830-8.
[93] Gyftopoulos K, Perimenis P. Sotiropoulou-Bonikou G, SakellaropoulosG. Varakis I. Barbalias GA. Immunohistochemical detection of retinoic acid receptor in prostate carcinoma: correlation with proliferative activity and tumor grade[J]. Int Urol Nephrol. 2000.32:263-269.
[94] Baron, S.. M. Manin. et al.Androgen receptor mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells[J]. J Biol Chem.2004. 279(15): 14579-86.
[95] Arce. F., O. Gatjens-Boniche. et al.Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2[J].Cancer Lett.2005. 229(2): 271-81.
[96] Mizejewski GJ, MacColl R. Alpha-fetoprotein growth inhibitory peptides: potential leads for cancer therapeutics[J]. Mol Cancer Ther .2003.2:1243-55.
[97] Vakharia D, Mizejewski GJ. Human alpha-fetoprotein peptides bind estrogen receptor and estradiol. and suppress breast cancer[J]. Breast Cancer Res Treat .2000.63:41-52.
[98] Muehlemann M, Miller KD. et al. Review of growth inhibitory peptide as a biotherapeutic agent for tumor growth, adhesion. and metastasis[J]. Cancer Metastasis Rev. 2005.24:441-67.
[99] Li MS, Li PF. et al. Alpha-fetoprotein stimulated the expression of some oncogenes in human hepatocellular carcinoma Bel 7402 cells[J]. World J Gastroenterol 2004.10:819-24.
[100] Gotoh M, Nakatani T. et al.Prediction of invasive activities in hepatocellular carcinomas with special reference to alpha-fetoprotein and desgamma-carboxyprothrombin[J]. Jpn J Clin Oncol 2003,33:522-6.
[101] Iida H, Honda M, et al.Ephrin-Al expression contributes to the malignant characteristics of alpha-fetoprotein producing hepatocellular carcinoma[J].Gut .2005.54:843-51.
[102] Ishigami S, Natsugoe S.et al.Biological aggressiveness of alpha-fetoprotein (AFP)-positive gastric cancer[J].Hepatogastroenterology.2006.53:338-41.
[103] Cavin, L. G., M. Venkatraman, et al. Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis[J] .Cancer Res.2004. 64(19): 7030-8.
[104] Pan, M. H., C. S. Lai, et al. Acacetin induces apoptosis in human gastric carcinoma cells accompanied by activation of caspase cascades and production of reactive oxygen species[J].J Agric Food Chem. 2005. 53(3): 620-30.
[105] Singh, R. P., P. Agrawal. et al.Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: structure-activity relationship with linarin and linarin acetate[J]. Carcinogenesis.2005, 26(4): 845-54.
[106] Shim, H. Y., J. H. Park, et al. Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation[J].Mol Cells.2007, 24(1): 95-104.
[107] Hsu, Y. L., P. L. Kuo, et al.Acacetin-induced cell cycle arrest and apoptosis in human non-small cell lung cancer A549 cells[J].Cancer Lett.2004. 212(1): 53-60.
[108] Zhang, L., R. Zhou, et al.Stress-induced change of mitochondria membrane potential regulated by genomic and non-genomic GR signaling: a possible mechanism for hippocampus atrophy in PTSD[J].Med Hypotheses.2006, 66(6): 1205-8.
[109] Safe, S. and K. Kim .Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways[J]. J Mol Endocrinol.2008.41(5): 263-75.
[110] Robinson-Rechavi. M.. H. Escriva Garcia, et al.The nuclear receptor superfami]y[J]. J Cell Sci .2003.116(Pt 4): 585-6.
[11] Valledor. A. F. and M. Ricote.Nuclear receptor signaling in macrophages[J]. Biochem Pharmacol.2004, 67(2):201-12.
[112] Dees. E. C. and M. J. Kennedy.Recent advances in systemic therapy for breast cancer[J].Curr Opin Oncol. 1998. 10(6): 517-22.
[113] Olefsky. J. M. and A. R. Saltiel.PPAR gamma and the treatment of insulin resistance[J]. Trends Endocrinol Metab.2000.11(9): 362-8.
[114] Dyer. M. J. PML/RAR alpha + ATRA = CR. A comment on acute promyelocytic leukaemia: molecular pathology and treatment[J]._Eur J Cancer. 1994. 30A(5): 573-4.
[115] Sun. T.. H. Takatsuki. et al.Detection of minimal residual disease in a patient with acute promyelocytic leukemia by RT-PCR: necessity of chemotherapy following ATRA therapy[J].Fukuoka Igaku Zasshi.1994. 85(2): 52-6.
[116] Han YH, Zhou H. et al. A unique cytoplasmic localization of RARgamma and its regulations[J].J Biol Chem. J Biol Chem. 2009 May 5. [Epub ahead of print]
[117] Benbrook. D.. E. Lernhardt. et al.A new retinoic acid receptor identified from a hepatocellular carcinoma[J].Nature .1988)333(6174): 669-72.
[118] Keller. H., C. Dreyer. et al .Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers[J]. Proc Natl Acad Sci U S A.. 1993. 90(6): 2160-4.
[119] Zhang. X.-K... J. M. Lehmann, B .et al. Ho-modimer formation of retinoid X receptor induced by 9-cis retinoic acid[J]. Nature (London) .1992.358:587-591.
[120] Lehmann. J. M.. X. K. Zhang. et al.Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching[J]. Mol Cell Biol. 1993.13(12): 7698-707.
[121] Lin. B., S. K. Kolluri. et al.Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3[J]. Cell. 2004.116(4): 527-40.