天然药物芹菜素拮抗Hsp90介导肿瘤杀伤的机制研究
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摘要
芹菜素(Apigenin)是一种广泛存在于多种水果蔬菜中的黄酮类化合物。体外和动物实验结果表明,芹菜素对乳腺癌、前列腺癌、结肠癌和白血病等多种肿瘤都具有拮抗作用,但对正常细胞却几乎没有影响。在关于其抗肿瘤作用机制的研究中,主要发现是能够增强活性氧水平、诱导促凋亡蛋白表达、改变细胞周期蛋白表达、阻断生存信号通路。芹菜素能够对细胞产生广泛的生物学效应,如抑制细胞增殖、阻滞细胞周期、诱导细胞凋亡等,但其具体的作用机制尚不是完全清楚。
热休克蛋白90(Heat shock protein, Hsp90)是细胞内最重要、含量最丰富的分子伴侣蛋白,在维持其底物蛋白的稳定构象与正常功能中起着重要作用。Hsp90的底物蛋白多是细胞内信号转导通路的关键蛋白成分,与肿瘤的发生、发展密切相关。Hsp90与其底物蛋白的相互作用需要一些辅助伴侣分子(co-chaperones)的参与,如Hsp70、Hop、Cdc37、p23等。其中,Cdc37能够特异性地募集多种蛋白激酶(如Raf-1、Akt、Src和Cdk4等)与Hsp90结合形成分子伴侣复合体来共同地维持底物蛋白的稳定性和激酶活性。然而Cdc37蛋白只有在CK2激酶的作用下发生Ser13位点的磷酸化修饰,才能变成活性形式参与形成分子伴侣复合体,提示抑制CK2的激酶活性有可能通过调节Cdc37的磷酸化来影响细胞内多项生命活动。
芹菜素能够竞争性地结合到CK2的ATP结合位点上,抑制其激酶活性。为探讨芹菜素是否能够通过抑制Cdc37的磷酸化来抑制Hsp90的分子伴侣功能,促进其多种底物蛋白降解,进而对细胞形成“多靶点打击”的效果,我们首先以前列腺癌细胞为模型,探讨了芹菜素对细胞内Hsp90蛋白的影响及其作用机制。
在前列腺癌细胞内,芹菜素能够抑制细胞的增殖、阻断细胞周期、并诱导细胞凋亡。在雄激素依赖性的LNCaP细胞内,芹菜素能够剂量和时间依赖性地促进雄激素受体(AR)经蛋白酶体通路降解,并抑制其转录激活活性。Western blot实验进一步证实芹菜素也能够促进Hsp90的其他底物蛋白经泛素蛋白酶体通路降解,而且这种作用与细胞凋亡无关。这说明芹菜素对Hsp90的分子伴侣功能具有抑制作用。ATP pull-down、免疫沉淀以及蛋白印迹实验结果证实,芹菜素既不能象GA那样直接与Hsp90结合、抑制蛋白与ATP结合的能力;也不能象FK228那样通过增强Hsp90的乙酰化来抑制Hsp90的分子伴侣功能。这说明芹菜素可能是通过间接的方式来抑制Hsp90的分子伴侣功能。
后续的实验结果显示,芹菜素能够下调前列腺癌细胞内CK2蛋白水平、并抑制其激酶活性。伴随着CK2激酶活性的阻断,Cdc37的磷酸化也随之降低,同时Cdc37与Hsp90及其底物蛋白(如AR和Cdk4)的结合也逐步减少,说明分子伴侣复合体结构被打破,底物蛋白与之解离并经蛋白酶体通路降解。采用RNA干扰的方法特异性地抑制Cdc37的表达后,多种Hsp90的底物蛋白也相应发生下调。该结果进一步证实Cdc37在维持Hsp90底物蛋白的稳定性中起着重要的作用。我们的实验还证实,芹菜素和Hsp90的抑制剂GA或Hsp70的抑制剂Quercetin联用时,对底物蛋白的清除作用更为彻底,提示同时阻断分子伴侣复合体的不同成分,可以协同地抑制其分子伴侣功能。
由于在多发性骨髓瘤细胞系及原代骨髓瘤细胞内CK2也呈高表达状态,并且细胞的生存依赖于其高激酶活性。我们又继续探讨了芹菜素对骨髓瘤细胞的影响。结果表明,芹菜素不仅能够抑制多种多发性骨髓瘤细胞系的增殖,还可以抑制细胞内的CK2激酶活性,促进多种Hsp90底物蛋白经蛋白酶体通路降解。实验还证实,芹菜素对细胞的杀伤效果与细胞内CK2蛋白的抑制程度有关。芹菜素能够抑制细胞内组成性和外源性细胞因子(如IL-6、IGF-1等)激活的生存信号通路;并活化死亡受体介导的Caspase-8/Caspase-3凋亡信号通路,最终诱导细胞发生细胞凋亡。对分离的原代骨髓瘤细胞研究发现,芹菜素能够选择性地抑制原代肿瘤细胞的增殖,但对正常的外周血单个核细胞(PBMC)没有影响。芹菜素也可以下调原代骨髓瘤细胞内的CK2蛋白水平,促进多种Hsp90底物蛋白降解,并激活Caspase-8/Caspase-3信号通路,诱导细胞凋亡。
综上所述,我们证实了芹菜素新的抗肿瘤作用机制:通过抑制Cdc37的磷酸化间接地抑制Hsp90的分子伴侣功能,导致分子伴侣复合体结构破坏,促进其底物蛋白经蛋白酶体通路降解,从而对细胞产生“多靶点打击”的效应。实验结果还证实“Hsp90/Cdc37分子伴侣复合体”为筛选新型的Hsp90功能抑制剂提供了新的作用靶点。
Apigenin, a common flavonoid, is found in a variety of fruits and vegetables, including parsley, onions, apple and certain seasonings. Apigenin has gained increasing attention due to its anti-tumor benefits, and has been shown to suppress proliferation in a wide variety of tumor cells, including those of the prostate, breast, and leukemia. Several mechanisms have been elucidated for its anti-tumor effect, such as deregulating cell cycle proteins, inducing apoptotic proteins, inhibiting fatty acid synthesis, producing reactive oxygen species, and inactiving survival signaling pathways. Apigeninn exhibits multiple effects on tumor cells, such as proliferative inhibition, cell cycle arrest and apoptosis induction, however, the underlying mechamisms are not fully elucidated.
Hsp90 (Heat shock protein 90), one of the most prominent chaperone, promotes the maturation and maintains the stability of numerous client proteins, most of which involving in the signal transduction, cell cycle and apoptosis. The interaction of Hsp90 and its client proteins also require several co-chaperones to maintain the chaperone complex, such as Hsp70, cdc37, Hop, p23, et al. Among the co-chaperones, Cdc37 is special because it is in charge to recruit a variety of proteins (such as Raf-1, Src, Akt and Cdk4 et al) to Hsp90 and maintains their stability and activities. Previous studies have shown that the Ser13 phosphorylation of Cdc37 induced by CK2 is essential for maintaining the function of Hsp90-Cdc37 complex, which suggestes that targeting CK2 may influence pleiotropic cellular functions by disturbing Cdc37 phosphorylation.
Apigenin can competitively binds to the ATP-binding site in CK2αand blocks its kinase activity. In order to explore wehter apigenin can influence the Hsp90 chaperone function by inhibition of Cdc37 phosphorylation, and promote the degradation of a variety of client proteins; we firstly choose the prostate cancer cells as the model to investigate the antitumor effect of apigenin.
In prostate cancer cells, apigenin showed the effects to inhibit cell proliferation, arrest cell cycle, and induce apoptosis. In androgen-dependent LNCaP cells, apigenin time and dose-dependetly induced the degradation of androgen receptor (AR) protein, an important Hsp90 client, and blocked its transactivation on PSA. Western blot analysis also showed that apigenin promoted the degradation of several other Hsp90 client proteins through ubiquitin-proteasome pathway, which is independent of apoptosis, indicating that apigenin could inhibit Hsp90 chaprone function. The results of ATP-Resin pull-down and immunoprecipitation plus western blotting showed that unlike GA or FK228, apigenin neither bindes with Hsp90 nor enhances its acetylation, suggesting that apigenin may influence Hsp90 function through other mechanims.
As a selective CK2 inhibitor, apigenin can down-regulate CK2 protein levels and inhibit its kinase activity. We noticed that accompany the decline of phosphorylation of Cdc37 protein, the interaction of Cdc37 with Hsp90 and its clients were also decreased, indicating that the molecular chaperone complex was disaaociated, which directly promoted the degradation of Hsp90 client proeins. The important role of Cdc37 on maintaining Hsp90 chapreon function was also comfirmed by Cdc37 siRNA. Additionally, apigenin showed synergic effect on depleting Hsp90 clients with either Hsp90 inhibitor GA or Hsp70 inhibitor quercetin, which indicating that Hsp90 complex has multiple targets.
Since CK2 protein is highly expresses in multiple myeloma (MM) cells, which plays a crucial role in controlling survival and sensitivity to chemotherapeutics of MM cells. We further detected the effect of apigenin on MM cells. The experiments revealed that apigenin inhibited proliferation of different multiple myeloma cell lines, inhibited CK2 kinase and promoted degradation of a variety of Hsp90 client proteins. The experiments also confirmed that the inhibitory effect of apigenin was correlated with the down-regulation of CK2 protein. Apigenin inactivated the intracellular and the extracellular cytokines-induced survival signaling pathways, and resulted in the activation of caspase-8/caspase-3 apoptosis pathways, finally induced cell apoptosis. Apigenin selectively inhibited the proliferation of purified primary MM cells, but had no effect on the normal PBMC cells. In the purified malignant plasma cells, apigenin also down-regulated CK2 protein and inhibited its kinase activity, promoted degradation of various Hsp90 client proteins, and induced cells to go apoptosis through casapase-dependent pathways.
In conclusion, our studies show for the first time that apigenin exerts its antitumor effect via indirectly inhibiting Hsp90 chaperone function. The mechanism involves inhibiting CK2-mediated Cdc37 phosphorylation, which resulting in Hsp90-Cdc37-clients complex disassociation. This study also supportes that targeting the Hsp90/Cdc37 chaperone complex is a new stratagem for finding new functional Hsp90 inhibitors.
热休克蛋白90(Heat shock protein, Hsp90)是细胞内最重要、含量最丰富的分子伴侣蛋白,在维持其底物蛋白的稳定构象与正常功能中起着重要作用。Hsp90的底物蛋白多是细胞内信号转导通路的关键蛋白成分,与肿瘤的发生、发展密切相关。Hsp90与其底物蛋白的相互作用需要一些辅助伴侣分子(co-chaperones)的参与,如Hsp70、Hop、Cdc37、p23等。其中,Cdc37能够特异性地募集多种蛋白激酶(如Raf-1、Akt、Src和Cdk4等)与Hsp90结合形成分子伴侣复合体来共同地维持底物蛋白的稳定性和激酶活性。然而Cdc37蛋白只有在CK2激酶的作用下发生Ser13位点的磷酸化修饰,才能变成活性形式参与形成分子伴侣复合体,提示抑制CK2的激酶活性有可能通过调节Cdc37的磷酸化来影响细胞内多项生命活动。
芹菜素能够竞争性地结合到CK2的ATP结合位点上,抑制其激酶活性。为探讨芹菜素是否能够通过抑制Cdc37的磷酸化来抑制Hsp90的分子伴侣功能,促进其多种底物蛋白降解,进而对细胞形成“多靶点打击”的效果,我们首先以前列腺癌细胞为模型,探讨了芹菜素对细胞内Hsp90蛋白的影响及其作用机制。
在前列腺癌细胞内,芹菜素能够抑制细胞的增殖、阻断细胞周期、并诱导细胞凋亡。在雄激素依赖性的LNCaP细胞内,芹菜素能够剂量和时间依赖性地促进雄激素受体(AR)经蛋白酶体通路降解,并抑制其转录激活活性。Western blot实验进一步证实芹菜素也能够促进Hsp90的其他底物蛋白经泛素蛋白酶体通路降解,而且这种作用与细胞凋亡无关。这说明芹菜素对Hsp90的分子伴侣功能具有抑制作用。ATP pull-down、免疫沉淀以及蛋白印迹实验结果证实,芹菜素既不能象GA那样直接与Hsp90结合、抑制蛋白与ATP结合的能力;也不能象FK228那样通过增强Hsp90的乙酰化来抑制Hsp90的分子伴侣功能。这说明芹菜素可能是通过间接的方式来抑制Hsp90的分子伴侣功能。
后续的实验结果显示,芹菜素能够下调前列腺癌细胞内CK2蛋白水平、并抑制其激酶活性。伴随着CK2激酶活性的阻断,Cdc37的磷酸化也随之降低,同时Cdc37与Hsp90及其底物蛋白(如AR和Cdk4)的结合也逐步减少,说明分子伴侣复合体结构被打破,底物蛋白与之解离并经蛋白酶体通路降解。采用RNA干扰的方法特异性地抑制Cdc37的表达后,多种Hsp90的底物蛋白也相应发生下调。该结果进一步证实Cdc37在维持Hsp90底物蛋白的稳定性中起着重要的作用。我们的实验还证实,芹菜素和Hsp90的抑制剂GA或Hsp70的抑制剂Quercetin联用时,对底物蛋白的清除作用更为彻底,提示同时阻断分子伴侣复合体的不同成分,可以协同地抑制其分子伴侣功能。
由于在多发性骨髓瘤细胞系及原代骨髓瘤细胞内CK2也呈高表达状态,并且细胞的生存依赖于其高激酶活性。我们又继续探讨了芹菜素对骨髓瘤细胞的影响。结果表明,芹菜素不仅能够抑制多种多发性骨髓瘤细胞系的增殖,还可以抑制细胞内的CK2激酶活性,促进多种Hsp90底物蛋白经蛋白酶体通路降解。实验还证实,芹菜素对细胞的杀伤效果与细胞内CK2蛋白的抑制程度有关。芹菜素能够抑制细胞内组成性和外源性细胞因子(如IL-6、IGF-1等)激活的生存信号通路;并活化死亡受体介导的Caspase-8/Caspase-3凋亡信号通路,最终诱导细胞发生细胞凋亡。对分离的原代骨髓瘤细胞研究发现,芹菜素能够选择性地抑制原代肿瘤细胞的增殖,但对正常的外周血单个核细胞(PBMC)没有影响。芹菜素也可以下调原代骨髓瘤细胞内的CK2蛋白水平,促进多种Hsp90底物蛋白降解,并激活Caspase-8/Caspase-3信号通路,诱导细胞凋亡。
综上所述,我们证实了芹菜素新的抗肿瘤作用机制:通过抑制Cdc37的磷酸化间接地抑制Hsp90的分子伴侣功能,导致分子伴侣复合体结构破坏,促进其底物蛋白经蛋白酶体通路降解,从而对细胞产生“多靶点打击”的效应。实验结果还证实“Hsp90/Cdc37分子伴侣复合体”为筛选新型的Hsp90功能抑制剂提供了新的作用靶点。
Apigenin, a common flavonoid, is found in a variety of fruits and vegetables, including parsley, onions, apple and certain seasonings. Apigenin has gained increasing attention due to its anti-tumor benefits, and has been shown to suppress proliferation in a wide variety of tumor cells, including those of the prostate, breast, and leukemia. Several mechanisms have been elucidated for its anti-tumor effect, such as deregulating cell cycle proteins, inducing apoptotic proteins, inhibiting fatty acid synthesis, producing reactive oxygen species, and inactiving survival signaling pathways. Apigeninn exhibits multiple effects on tumor cells, such as proliferative inhibition, cell cycle arrest and apoptosis induction, however, the underlying mechamisms are not fully elucidated.
Hsp90 (Heat shock protein 90), one of the most prominent chaperone, promotes the maturation and maintains the stability of numerous client proteins, most of which involving in the signal transduction, cell cycle and apoptosis. The interaction of Hsp90 and its client proteins also require several co-chaperones to maintain the chaperone complex, such as Hsp70, cdc37, Hop, p23, et al. Among the co-chaperones, Cdc37 is special because it is in charge to recruit a variety of proteins (such as Raf-1, Src, Akt and Cdk4 et al) to Hsp90 and maintains their stability and activities. Previous studies have shown that the Ser13 phosphorylation of Cdc37 induced by CK2 is essential for maintaining the function of Hsp90-Cdc37 complex, which suggestes that targeting CK2 may influence pleiotropic cellular functions by disturbing Cdc37 phosphorylation.
Apigenin can competitively binds to the ATP-binding site in CK2αand blocks its kinase activity. In order to explore wehter apigenin can influence the Hsp90 chaperone function by inhibition of Cdc37 phosphorylation, and promote the degradation of a variety of client proteins; we firstly choose the prostate cancer cells as the model to investigate the antitumor effect of apigenin.
In prostate cancer cells, apigenin showed the effects to inhibit cell proliferation, arrest cell cycle, and induce apoptosis. In androgen-dependent LNCaP cells, apigenin time and dose-dependetly induced the degradation of androgen receptor (AR) protein, an important Hsp90 client, and blocked its transactivation on PSA. Western blot analysis also showed that apigenin promoted the degradation of several other Hsp90 client proteins through ubiquitin-proteasome pathway, which is independent of apoptosis, indicating that apigenin could inhibit Hsp90 chaprone function. The results of ATP-Resin pull-down and immunoprecipitation plus western blotting showed that unlike GA or FK228, apigenin neither bindes with Hsp90 nor enhances its acetylation, suggesting that apigenin may influence Hsp90 function through other mechanims.
As a selective CK2 inhibitor, apigenin can down-regulate CK2 protein levels and inhibit its kinase activity. We noticed that accompany the decline of phosphorylation of Cdc37 protein, the interaction of Cdc37 with Hsp90 and its clients were also decreased, indicating that the molecular chaperone complex was disaaociated, which directly promoted the degradation of Hsp90 client proeins. The important role of Cdc37 on maintaining Hsp90 chapreon function was also comfirmed by Cdc37 siRNA. Additionally, apigenin showed synergic effect on depleting Hsp90 clients with either Hsp90 inhibitor GA or Hsp70 inhibitor quercetin, which indicating that Hsp90 complex has multiple targets.
Since CK2 protein is highly expresses in multiple myeloma (MM) cells, which plays a crucial role in controlling survival and sensitivity to chemotherapeutics of MM cells. We further detected the effect of apigenin on MM cells. The experiments revealed that apigenin inhibited proliferation of different multiple myeloma cell lines, inhibited CK2 kinase and promoted degradation of a variety of Hsp90 client proteins. The experiments also confirmed that the inhibitory effect of apigenin was correlated with the down-regulation of CK2 protein. Apigenin inactivated the intracellular and the extracellular cytokines-induced survival signaling pathways, and resulted in the activation of caspase-8/caspase-3 apoptosis pathways, finally induced cell apoptosis. Apigenin selectively inhibited the proliferation of purified primary MM cells, but had no effect on the normal PBMC cells. In the purified malignant plasma cells, apigenin also down-regulated CK2 protein and inhibited its kinase activity, promoted degradation of various Hsp90 client proteins, and induced cells to go apoptosis through casapase-dependent pathways.
In conclusion, our studies show for the first time that apigenin exerts its antitumor effect via indirectly inhibiting Hsp90 chaperone function. The mechanism involves inhibiting CK2-mediated Cdc37 phosphorylation, which resulting in Hsp90-Cdc37-clients complex disassociation. This study also supportes that targeting the Hsp90/Cdc37 chaperone complex is a new stratagem for finding new functional Hsp90 inhibitors.
引文
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27 Singh RP, Agarwal R. Mechanism of action of novel agents for prostate cancer chemoprevention. Endocrine-related Cancer, 2006, 13(3):751-78
28 Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinaseyAkt pathway. Proc Natl Acad Sci U S A, 1998, 95(26):15587-91.
29 Ren F, Zhang S, Mitchell SH, et al. Tea ployphenols down-regualte the expression of the androgen receptor in LNCaP prostate cancer cells. Oncogene, 2000, 19(4):1924-32.
30 Knekt P, Kumpulainen J, Jarvinen RF, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr, 2002, 76(8):560-8.
31 Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003; 3(10): 768-80.
32 Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med, 2003, 349(3):215-24.
33 Shukla S, Gupta S. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol Cancer Ther, 2006, 5 (4):843-52
34 Shukla S, Mishra A, Fu P, et al. Upregulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. FASEB J, 2005, 19(14):2042-204.
35 Zhu W, Zhang JS, Young CY. Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP. Carcinogenesis, 2001, 22(9): 1399–403.
36 Jiang C, Lee HJ, Li GX, et al. Potent anti-androgen and androgen receptor activities of an Angelica gigas-containing herbal formulation: identification of decursin as a novel and active compound with implications for prevention and treatment of prostate cancer. Cancer Res, 2006, 66(1): 453-63.
37 Bektic J, Guggenberger R, Eder IE, et al. Molecular effects of the isoflavonoid genistein in prostate cancer. Clinical Prostate Cancer, 2005, 4(2): 124-9.
38 Xing N, Chen Y, Mitchell SH, et al. Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis, 2001, 22(3): 409-14.
39 Grossmann ME, Huang H, Tindall DJ. Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst, 2001, 93(22): 1687-97.
40 Vanaja DK, Mitchell SH, Toft DO, et al. Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 2002, 7(1):55-64.
41 Tong W, Cordon-Cardo C, Agus DB, et al. 17-Allylamino- 17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res, 2002, 8(5):986-93.
42 Basak S, Pookot D, Noonan, EJ, et al. Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Mol Cancer Ther, 2008, 7(10):3195-202.
43 Miyata Y, Nishida E. CK2 binds, phosphorylateds, and regulateds its pivotal substrate Cdc37, an Hsp90-cochaperone. Mol Cell Biochem, 2005, 274(2):171-9.
44 Zhang T, Hamza A, Cao X, et al. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther, 2008, 7(1):162-70.
45 Litchfield DW. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 2003; 369 (Pt1):1-15.
46 Guerra B, Issinger OG. Protein kinase CK2 in human disease. Curr Med Chem, 2008, 15(19): 1870-86.
47 Vaughan CK, Mollapour M, Smith JR, et al. Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol Cell, 2008, 31(6):886-95
48 Hessenauer A, Montenarh M, G?tz C. Inhibition of CK2 activity provokes different responses in hormone-sensitive and hormone-refractory prostate cancer cells. Int J Oncol, 2003, 22(6):1263-70.
49 Li X, Guan B, Maghami S, Bieberich CJ. NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Mol Cell Biol, 2006, 26(8):3008-17.
50 Soncin F, Zhang X, Chu B et al. Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2. Biochem Biophys Res Commun, 2003, 303(2):700-6.
51 Wang GL, Jiang BH, Rue EA, et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A, 1995, 92(12):5510-4.
52 Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-1a to the von Hippel-Lindau ubiquitilation complex by O2-regulated prolyl hydroxylation. Science, 2001, 292(5516):468-72.
53 Isaacs JS, Jung YJ, Mimnaugh EG, et al. Hsp90 regulateds a von hippel landau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem, 2002, 277(33):29936-44.
54 Kong X, Lin Z, Liang D, et al. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1α. Mol Cell Biol, 2006, 26(6):2019-28.
55 Osada M, Imaoka S, Funae Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1αprotein. FEBS Lett, 2004, 575(1-3):59-63
56 Fang J, Zhou Q, Liu LZ, et al. Apigenin inhibits tumor angiogenesis through decreasing HIF-1αand VEGF expression. Carcinogenesis, 2007, 28(4):858-64.
57 Fang J, Xia C, Cao Z, et al. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways, FASEB J, 2005,19(3):342-53.
58 Hideshima T, Bergsagel PL, Kuehl WM, et al. Advances in biology of multiple myeloma: clinical applications. Blood, 2004, 104(3):607-18.
59 Chng WJ, Lau LG, Yusof N, et al. Targeted therapy in multiple myeloma. Cancer Control, 2005, 12(2): 91-104.
60 Piazza FA, Ruzzene M, Currieri C, et al. Multiple myeloma cell survival relies on high activity of protein kinase CK2. Blood, 2006, 108(5): 1698-707.
61 Ahmed K, Davis AT, Wang H, et al. Significance of protein kinase CK2 nuclear signaling in neoplasia. J Cell Biochem Suppl, 2000, 35:130-5.
62 Kim JS, Eom JI, Cheong JW, et al. Protein kinase CK2αas an unfavorable prognositic marker and novel therapeutic target in acute myeloma. Leukemia, Clin Cancer Res, 2007, 13(3):1019-28
63 Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumor selectivity on Hsp90 inhibitors. Nature, 2003, 425(6956):407-10.
64 Dalton WS. The tumor microenvironment: focus on myeloma. Cancer Treat Rev, 2003, 29 Suppl 1:11-9.
65 Nefedova Y, Landowski TH, Dalton WS. Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia, 2003, 17(6): 1175-82.
66 Catlett-falcone R, Landowski TH, Oshiro MM, et al. constitutive activation of STAT-3 signaling confers resistance to apoptosis in human U266 myeloma cells.Immunity, 1999, 10(1):105-15.
67 Mitsiades CS, Mitsiades N, poulaki V, et al. Activation of NF-kappa B and upregulation of intracellular anti-apoptotic protins via the IGF-1/Akt signaling in human multiple myeloma cells:therapeutic implications. Oncogene, 2002, 21(37):5673-83.
68 Hideshima T, Mitsiades C, Akiyama M, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood, 2003, 101(4):1530-4.
69 Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res, 2001, 61(7):3071-6
70 Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med, 1999, 341(21):1565-71.
71 Hayashi T, Hideshima T, Akiyama M, et al. Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow microenvironment. Mol Cancer Ther, 2002, 1(10):851-60.
72 Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A, 2002, 99(22):14374-9.
73 Liu Q, Hilsenbeck S, Gazitt Y. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase 8 or 9 and synergy with APO2/TRAIL. Blood, 2003, 101(10): 4078-87.
74 Muto A, Hori M, Sasaki Y, et al. Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor. Mol Cancer Ther, 2007, 6(3):987-94.
75 Shammas MA, Neri P, Koley H, et al. Specific killing of multiple myeloma cells by (-)-epigallocatechin-3-gallate extracted from green tea: biologic activity and therapeutic implications. Blood, 2006, 108(8):2804-10.
76 Bhardwaj A, Sethi G, Vadhan-Raj S, et al. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation ofSTAT3 and nuclear factor-κB–regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood, 2007, 109(6):2293-302.
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2 Patel D, Shukla S, Gupta S. Apigenin and caner chemoprevention: progress, potential and promise. Inter J Oncol, 2007, 30(1):233-45.
3 Gupta S, Afaq F, Mukhtar H. Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun, 2001, 287(4):914-200.
4 Morrissey C, O'Neill A, Spengler B, Christoffel V, Fitzpatrick JM, Watson RW. Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in prostate epithelial cells. Prostate 2005, 63 (2):131-42.
5 Gupta S, Afaq F, Mukhtar H. Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human protstate carcinoma cells. Oncogene, 2002, 21(23): 3727-38
6 Shukla S, Gupta S. Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell Cycle 2007, 6 (9):1102-14
7 Shukla S, Gupta S. Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol Carcinog, 2004, 39 (2):114-26.
8 Shukla S, Gupta S. Suppression of constitutive and tumor necrosis factor alpha-induced nuclear factor (NF)-kappa B activation and induction of apoptosis by apigenin in human prostate carcinoma PC-3 cells: correlation with down-regulation of NF-kappaB-responsive genes. Clin Cancer Res, 2004, 10 (9):3169-78.
9 Shukla S, Maclennan GT, Flask CA, Fu P, Mishra A, Resnick MI, et al. Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. Cancer Res, 2007, 67 (14): 6925-35.
10 Neckers L, Ivy SP. Heat shock protein 90. Curr Opin Oncol, 2003, 15(6): 419-24.
11 Bagatell R, Whitesell L. Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther, 2004, 3 (8):1021-30.
12 Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med, 2002, 8 (Suppl 4): S55-61.
13 Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by Depsipeptide FR901228. J Natl Cancer Inst, 2002, 94 (7): 504-13.
14 Chen L, Meng S, Wang H, et al. Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. Mol Cancer Ther, 2005, 4 (9): 1311-9.
15 Hieronymus H, Lamb J, Ross KN, et al. Gene expression signature-based chemical genomic prediction identifies a novel class of Hsp90 pathway modulators. Cancer Cell, 2006, 10(4):321-30.
16 Whitesell L, Lindquist SL. Hsp90 and the chaperoning of cancer. Nature Rev Cancer, 2005, 5 (10):761-72
17 Pearl LH. Hsp90 and Cdc37- a chaperone cancer conspiracy. Curr Opin Genet Dev 2005; 15 (1): 55-61.
18 Gray PJ, Stevenson MA, Galderwood SK. Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells. Cancer Res, 2007, 67(24):11942-50.
19 Smith JR, Clarke PA, Billy E, et al. Silencing the cochaperone CDC37 destabilises kinase clients and sensitises cancer cells to HSP90 inhibitor. Oncogene, 2009, 28 (2): 157-69.
20 Bandhakavi S, Mccann RO, Hanna DE, et al. A positive feedback loop between protein kinase CKII and Cdc37 promotes the activity of multiple protein kinases.J Biol Chem, 2003, 278(5): 2829-36.
21 Shao J, Prince T, Hartson SD, et al. Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. J Biol Chem, 2003, 278(40):38117-20.
22 Miyata Y, Nishida E. CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37. Mol Cell Biol, 2004, 24(9):4065-74.
23 Romieu-Mourez R, Landesman-Bollag E, Seldin DC, et al. Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer. Cancer Res, 2001, 61(9):3810-8.
24 Shen J, Channavajhala P, Seldin DC, et al. Phosphorylation by the protein kinase CK2 promotes calpain-mediated degradation of I-kappa B alpha. J Immunol, 2001, 167(9):4919-25.
25 Jemal A, Siegel R, Ward E, et al. Cancer statistics 2007. CA Cancer J Clin 2007, 57:43-66.
26 Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev, 2004, 25(2):276-308.
27 Singh RP, Agarwal R. Mechanism of action of novel agents for prostate cancer chemoprevention. Endocrine-related Cancer, 2006, 13(3):751-78
28 Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinaseyAkt pathway. Proc Natl Acad Sci U S A, 1998, 95(26):15587-91.
29 Ren F, Zhang S, Mitchell SH, et al. Tea ployphenols down-regualte the expression of the androgen receptor in LNCaP prostate cancer cells. Oncogene, 2000, 19(4):1924-32.
30 Knekt P, Kumpulainen J, Jarvinen RF, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr, 2002, 76(8):560-8.
31 Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003; 3(10): 768-80.
32 Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med, 2003, 349(3):215-24.
33 Shukla S, Gupta S. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol Cancer Ther, 2006, 5 (4):843-52
34 Shukla S, Mishra A, Fu P, et al. Upregulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. FASEB J, 2005, 19(14):2042-204.
35 Zhu W, Zhang JS, Young CY. Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP. Carcinogenesis, 2001, 22(9): 1399–403.
36 Jiang C, Lee HJ, Li GX, et al. Potent anti-androgen and androgen receptor activities of an Angelica gigas-containing herbal formulation: identification of decursin as a novel and active compound with implications for prevention and treatment of prostate cancer. Cancer Res, 2006, 66(1): 453-63.
37 Bektic J, Guggenberger R, Eder IE, et al. Molecular effects of the isoflavonoid genistein in prostate cancer. Clinical Prostate Cancer, 2005, 4(2): 124-9.
38 Xing N, Chen Y, Mitchell SH, et al. Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis, 2001, 22(3): 409-14.
39 Grossmann ME, Huang H, Tindall DJ. Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst, 2001, 93(22): 1687-97.
40 Vanaja DK, Mitchell SH, Toft DO, et al. Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 2002, 7(1):55-64.
41 Tong W, Cordon-Cardo C, Agus DB, et al. 17-Allylamino- 17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res, 2002, 8(5):986-93.
42 Basak S, Pookot D, Noonan, EJ, et al. Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Mol Cancer Ther, 2008, 7(10):3195-202.
43 Miyata Y, Nishida E. CK2 binds, phosphorylateds, and regulateds its pivotal substrate Cdc37, an Hsp90-cochaperone. Mol Cell Biochem, 2005, 274(2):171-9.
44 Zhang T, Hamza A, Cao X, et al. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther, 2008, 7(1):162-70.
45 Litchfield DW. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 2003; 369 (Pt1):1-15.
46 Guerra B, Issinger OG. Protein kinase CK2 in human disease. Curr Med Chem, 2008, 15(19): 1870-86.
47 Vaughan CK, Mollapour M, Smith JR, et al. Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol Cell, 2008, 31(6):886-95
48 Hessenauer A, Montenarh M, G?tz C. Inhibition of CK2 activity provokes different responses in hormone-sensitive and hormone-refractory prostate cancer cells. Int J Oncol, 2003, 22(6):1263-70.
49 Li X, Guan B, Maghami S, Bieberich CJ. NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Mol Cell Biol, 2006, 26(8):3008-17.
50 Soncin F, Zhang X, Chu B et al. Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2. Biochem Biophys Res Commun, 2003, 303(2):700-6.
51 Wang GL, Jiang BH, Rue EA, et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A, 1995, 92(12):5510-4.
52 Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-1a to the von Hippel-Lindau ubiquitilation complex by O2-regulated prolyl hydroxylation. Science, 2001, 292(5516):468-72.
53 Isaacs JS, Jung YJ, Mimnaugh EG, et al. Hsp90 regulateds a von hippel landau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem, 2002, 277(33):29936-44.
54 Kong X, Lin Z, Liang D, et al. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1α. Mol Cell Biol, 2006, 26(6):2019-28.
55 Osada M, Imaoka S, Funae Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1αprotein. FEBS Lett, 2004, 575(1-3):59-63
56 Fang J, Zhou Q, Liu LZ, et al. Apigenin inhibits tumor angiogenesis through decreasing HIF-1αand VEGF expression. Carcinogenesis, 2007, 28(4):858-64.
57 Fang J, Xia C, Cao Z, et al. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways, FASEB J, 2005,19(3):342-53.
58 Hideshima T, Bergsagel PL, Kuehl WM, et al. Advances in biology of multiple myeloma: clinical applications. Blood, 2004, 104(3):607-18.
59 Chng WJ, Lau LG, Yusof N, et al. Targeted therapy in multiple myeloma. Cancer Control, 2005, 12(2): 91-104.
60 Piazza FA, Ruzzene M, Currieri C, et al. Multiple myeloma cell survival relies on high activity of protein kinase CK2. Blood, 2006, 108(5): 1698-707.
61 Ahmed K, Davis AT, Wang H, et al. Significance of protein kinase CK2 nuclear signaling in neoplasia. J Cell Biochem Suppl, 2000, 35:130-5.
62 Kim JS, Eom JI, Cheong JW, et al. Protein kinase CK2αas an unfavorable prognositic marker and novel therapeutic target in acute myeloma. Leukemia, Clin Cancer Res, 2007, 13(3):1019-28
63 Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumor selectivity on Hsp90 inhibitors. Nature, 2003, 425(6956):407-10.
64 Dalton WS. The tumor microenvironment: focus on myeloma. Cancer Treat Rev, 2003, 29 Suppl 1:11-9.
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