| |
Melittin exerts antitumorigenic effects in human MM1.S multiple myeloma cells through the suppression of AKT/mTOR/S6K1/4E-BP1 signaling cascades
- 作者:Chulwon Kim (1)
Dong Sub Kim (1) Dongwoo Nam (1) Sung-Hoon Kim (1) Bum Sang Shim (1) Kwang Seok Ahn (1)
1. Department of Korean Pathology ; College of Korean Medicine ; Kyung Hee University ; 1 Hoegidong Dongdaemungu ; Seoul ; 130-701 ; Republic of Korea
- 关键词:Melittin ; AKT/mTOR/S6K1/4E ; BP1 ; Apoptosis ; MM1.S ; Multiple myeloma
- 刊名:Oriental Pharmacy and Experimental Medicine
- 出版年:2015
- 出版时间:March 2015
- 年:2015
- 卷:15
- 期:1
- 页码:33-44
- 全文大小:807 KB
- 参考文献:1. Aggarwal, BB (2006) Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci 1091: pp. 151-169 10.1196/annals.1378.063" target="_blank" title="It opens in new window">CrossRef
2. Ahn, KS, Sethi, G, Aggarwal, BB (2007) Nuclear factor-kappa B: from clone to clinic. Curr Mol Med 7: pp. 619-637 10.2174/156652407782564363" target="_blank" title="It opens in new window">CrossRef 3. Banko, JL, Poulin, F, Hou, L, DeMaria, CT, Sonenberg, N, Klann, E (2005) The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J Neurosci 25: pp. 9581-9590 10.1523/JNEUROSCI.2423-05.2005" target="_blank" title="It opens in new window">CrossRef 4. Barlund, M (2000) Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J Natl Cancer Inst 92: pp. 1252-1259 10.1093/jnci/92.15.1252" target="_blank" title="It opens in new window">CrossRef 5. Bartlett, JM (2010) Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies: current status and future directions. Clin Breast Cancer 10: pp. S86-S95 10.3816/CBC.2010.s.017" target="_blank" title="It opens in new window">CrossRef 6. Berset, C, Trachsel, H, Altmann, M (1998) The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 95: pp. 4264-4269 10.1073/pnas.95.8.4264" target="_blank" title="It opens in new window">CrossRef 7. Bortner, CD, Oldenburg, NB, Cidlowski, JA (1995) The role of DNA fragmentation in apoptosis. Trends Cell Biol 5: pp. 21-26 10.1016/S0962-8924(00)88932-1" target="_blank" title="It opens in new window">CrossRef 8. Brunet, A (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: pp. 857-868 10.1016/S0092-8674(00)80595-4" target="_blank" title="It opens in new window">CrossRef 9. Campone, M (2009) Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer 100: pp. 315-321 10.1038/sj.bjc.6604851" target="_blank" title="It opens in new window">CrossRef 10. Chu, ST (2007) Phospholipase A2-independent Ca2+ entry and subsequent apoptosis induced by melittin in human MG63 osteosarcoma cells. Life Sci 80: pp. 364-369 10.1016/j.lfs.2006.09.024" target="_blank" title="It opens in new window">CrossRef 11. Collado, M (2000) Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. J Biol Chem 275: pp. 21960-21968 10.1074/jbc.M000759200" target="_blank" title="It opens in new window">CrossRef 12. Dancey, JE (2006) Therapeutic targets: MTOR and related pathways. Cancer Biol Ther 5: pp. 1065-1073 10.4161/cbt.5.9.3175" target="_blank" title="It opens in new window">CrossRef 13. Datta, SR, Dudek, H, Tao, X, Masters, S, Fu, H, Gotoh, Y, Greenberg, ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: pp. 231-241 10.1016/S0092-8674(00)80405-5" target="_blank" title="It opens in new window">CrossRef 14. DeBerardinis, RJ, Lum, JJ, Hatzivassiliou, G, Thompson, CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: pp. 11-20 10.1016/j.cmet.2007.10.002" target="_blank" title="It opens in new window">CrossRef 15. Ehrenberg, B, Montana, V, Wei, MD, Wuskell, JP, Loew, LM (1988) Membrane potential can be determined in individual cells from the nernstian distribution of cationic dyes. Biophys J 53: pp. 785-794 10.1016/S0006-3495(88)83158-8" target="_blank" title="It opens in new window">CrossRef 16. Ferre, R, Melo, MN, Correia, AD, Feliu, L, Bardaji, E, Planas, M, Castanho, M (2009) Synergistic effects of the membrane actions of cecropin-melittin antimicrobial hybrid peptide BP100. Biophys J 96: pp. 1815-1827 10.1016/j.bpj.2008.11.053" target="_blank" title="It opens in new window">CrossRef 17. Gao, N, Zhang, Z, Jiang, BH, Shi, X (2003) Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun 310: pp. 1124-1132 10.1016/j.bbrc.2003.09.132" target="_blank" title="It opens in new window">CrossRef 18. Gingras, AC (1999) Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 13: pp. 1422-1437 10.1101/gad.13.11.1422" target="_blank" title="It opens in new window">CrossRef 19. Gingras, AC, Raught, B, Sonenberg, N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68: pp. 913-963 10.1146/annurev.biochem.68.1.913" target="_blank" title="It opens in new window">CrossRef 20. Gold, R, Schmied, M, Giegerich, G, Breitschopf, H, Hartung, HP, Toyka, KV, Lassmann, H (1994) Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Investig J Tech Methods Pathol 71: pp. 219-225 21. Gross, A, McDonnell, JM, Korsmeyer, SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13: pp. 1899-1911 10.1101/gad.13.15.1899" target="_blank" title="It opens in new window">CrossRef 22. Hay, N (2005) The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8: pp. 179-183 10.1016/j.ccr.2005.08.008" target="_blank" title="It opens in new window">CrossRef 23. Hay, N, Sonenberg, N (2004) Upstream and downstream of mTOR. Genes Dev 18: pp. 1926-1945 10.1101/gad.1212704" target="_blank" title="It opens in new window">CrossRef 24. Inoki, K, Corradetti, MN, Guan, KL (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37: pp. 19-24 10.1038/ng1494" target="_blank" title="It opens in new window">CrossRef 25. Jayaraman, S (2005) Flow cytometric determination of mitochondrial membrane potential changes during apoptosis of T lymphocytic and pancreatic beta cell lines: comparison of tetramethylrhodamineethylester (TMRE), chloromethyl-X-rosamine (H2-CMX-Ros) and MitoTracker Red 580 (MTR580). J Immunol Methods 306: pp. 68-79 10.1016/j.jim.2005.07.024" target="_blank" title="It opens in new window">CrossRef 26. Jo, M (2012) Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway. Toxicol Appl Pharmacol 258: pp. 72-81 10.1016/j.taap.2011.10.009" target="_blank" title="It opens in new window">CrossRef 27. Kang, SS, Pak, SC, Choi, SH (2002) The effect of whole bee venom on arthritis. Am J Chin Med 30: pp. 73-80 10.1142/S0192415X02000089" target="_blank" title="It opens in new window">CrossRef 28. Kevil, C, Carter, P, Hu, B, DeBenedetti, A (1995) Translational enhancement of FGF-2 by eIF-4 factors, and alternate utilization of CUG and AUG codons for translation initiation. Oncogene 11: pp. 2339-2348 29. Kevil, CG, Benedetti, A, Payne, DK, Coe, LL, Laroux, FS, Alexander, JS (1996) Translational regulation of vascular permeability factor by eukaryotic initiation factor 4E: implications for tumor angiogenesis. Int J Cancer 65: pp. 785-790 10.1002/(SICI)1097-0215(19960315)65:6<785::AID-IJC14>3.0.CO;2-3" target="_blank" title="It opens in new window">CrossRef 30. Klocek, G, Seelig, J (2008) Melittin interaction with sulfated cell surface sugars. Biochemistry 47: pp. 2841-2849 10.1021/bi702258z" target="_blank" title="It opens in new window">CrossRef 31. Kwon, YB (2002) The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats. Life Sci 71: pp. 191-204 10.1016/S0024-3205(02)01617-X" target="_blank" title="It opens in new window">CrossRef 32. Lang, CH, Frost, RA (2005) Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. J Cell Physiol 203: pp. 144-155 10.1002/jcp.20207" target="_blank" title="It opens in new window">CrossRef 33. Lazarev, VN, Shkarupeta, MM, Kostryukova, ES, Levitskii, SA, Titova, GA, Akopian, TA, Govorun, VM (2007) Recombinant plasmid constructs expressing gene for antimicrobial peptide melittin for the therapy of Mycoplasma and chlamydia infections. Bull Exp Biol Med 144: pp. 452-456 10.1007/s10517-007-0350-1" target="_blank" title="It opens in new window">CrossRef 34. Lee, JD, Kim, SY, Kim, TW, Lee, SH, Yang, HI, Lee, DI, Lee, YH (2004) Anti-inflammatory effect of bee venom on type II collagen-induced arthritis. Am J Chin Med 32: pp. 361-367 10.1142/S0192415X04002016" target="_blank" title="It opens in new window">CrossRef 35. Lee, JD, Park, HJ, Chae, Y, Lim, S (2005) An overview of bee venom acupuncture in the treatment of arthritis evid based complement. Altern Med 2: pp. 79-84 36. Lee, JY, Kang, SS, Kim, JH, Bae, CS, Choi, SH (2005) Inhibitory effect of whole bee venom in adjuvant-induced arthritis. In Vivo 19: pp. 801-805 37. Lin, CJ, Cencic, R, Mills, JR, Robert, F, Pelletier, J (2008) c-Myc and eIF4F are components of a feedforward loop that links transcription and translation. Cancer Res 68: pp. 5326-5334 10.1158/0008-5472.CAN-07-5876" target="_blank" title="It opens in new window">CrossRef 38. Liu, S (2008) Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology 47: pp. 1964-1973 10.1002/hep.22240" target="_blank" title="It opens in new window">CrossRef 39. Liu, SI (2008) Melittin-induced [Ca2+]i increases and subsequent death in canine renal tubular cells. Hum Exp Toxicol 27: pp. 417-424 10.1177/0960327108094606" target="_blank" title="It opens in new window">CrossRef 40. LoPiccolo, J, Blumenthal, GM, Bernstein, WB, Dennis, PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11: pp. 32-50 10.1016/j.drup.2007.11.003" target="_blank" title="It opens in new window">CrossRef 41. Madrid, LV, Mayo, MW, Reuther, JY, Baldwin, AS (2001) Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 276: pp. 18934-18940 10.1074/jbc.M101103200" target="_blank" title="It opens in new window">CrossRef 42. McAuliffe, PF, Meric-Bernstam, F, Mills, GB, Gonzalez-Angulo, AM (2010) Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer 10: pp. S59-S65 10.3816/CBC.2010.s.013" target="_blank" title="It opens in new window">CrossRef 43. Moon, DO (2007) Bee venom and melittin reduce proinflammatory mediators in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol 7: pp. 1092-1101 10.1016/j.intimp.2007.04.005" target="_blank" title="It opens in new window">CrossRef 44. Moon, DO, Park, SY, Choi, YH, Kim, ND, Lee, C, Kim, GY (2008) Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells. Toxicon 51: pp. 112-120 10.1016/j.toxicon.2007.08.015" target="_blank" title="It opens in new window">CrossRef 45. Mosmann, T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: pp. 55-63 10.1016/0022-1759(83)90303-4" target="_blank" title="It opens in new window">CrossRef 46. Nawroth, R (2011) S6K1 and 4E-BP1 are independent regulated and control cellular growth in bladder cancer. PLoS One 6: pp. e27509 10.1371/journal.pone.0027509" target="_blank" title="It opens in new window">CrossRef 47. Nicoletti, I, Migliorati, G, Pagliacci, MC, Grignani, F, Riccardi, C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139: pp. 271-279 10.1016/0022-1759(91)90198-O" target="_blank" title="It opens in new window">CrossRef 48. Noh, WC (2004) Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10: pp. 1013-1023 10.1158/1078-0432.CCR-03-0043" target="_blank" title="It opens in new window">CrossRef 49. Park, S (2005) Molecular cloning and characterization of the human AKT1 promoter uncovers its up-regulation by the Src/Stat3 pathway. J Biol Chem 280: pp. 38932-38941 10.1074/jbc.M504011200" target="_blank" title="It opens in new window">CrossRef 50. Park, HJ (2007) Melittin inhibits inflammatory target gene expression and mediator generation via interaction with IkappaB kinase. Biochem Pharmacol 73: pp. 237-247 10.1016/j.bcp.2006.09.023" target="_blank" title="It opens in new window">CrossRef 51. Park, HJ (2008) JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-kappaB activation by melittin. J Inflamm (Lond) 5: pp. 7 10.1186/1476-9255-5-7" target="_blank" title="It opens in new window">CrossRef 52. Park, JH (2010) Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression. Mol Cells 29: pp. 209-215 10.1007/s10059-010-0028-9" target="_blank" title="It opens in new window">CrossRef 53. Park, MH (2011) Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase pathway via inactivation of NF-kappaB. Prostate 71: pp. 801-812 10.1002/pros.21296" target="_blank" title="It opens in new window">CrossRef 54. Pullen, N, Thomas, G (1997) The modular phosphorylation and activation of p70s6k. FEBS Lett 410: pp. 78-82 10.1016/S0014-5793(97)00323-2" target="_blank" title="It opens in new window">CrossRef 55. Rosenwald, IB, Lazaris-Karatzas, A, Sonenberg, N, Schmidt, EV (1993) Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol 13: pp. 7358-7363 56. Sengupta, D, Leontiadou, H, Mark, AE, Marrink, SJ (2008) Toroidal pores formed by antimicrobial peptides show significant disorder. Biochim Biophys Acta 1778: pp. 2308-2317 10.1016/j.bbamem.2008.06.007" target="_blank" title="It opens in new window">CrossRef 57. Shantz, LM, Pegg, AE (1994) Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res 54: pp. 2313-2316 58. Song, CC, Lu, X, Cheng, BB, Du, J, Li, B, Ling, CQ (2007) Effects of melittin on growth and angiogenesis of human hepatocellular carcinoma BEL-7402 cell xenografts in nude mice. Ai Zheng 26: pp. 1315-1322 59. Strimpakos, AS, Karapanagiotou, EM, Saif, MW, Syrigos, KN (2009) The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 35: pp. 148-159 10.1016/j.ctrv.2008.09.006" target="_blank" title="It opens in new window">CrossRef 60. Tee, AR, Proud, CG (2000) DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling. Oncogene 19: pp. 3021-3031 10.1038/sj.onc.1203622" target="_blank" title="It opens in new window">CrossRef 61. Tee, AR, Proud, CG (2001) Staurosporine inhibits phosphorylation of translational regulators linked to mTOR. Cell Death Differ 8: pp. 841-849 10.1038/sj.cdd.4400876" target="_blank" title="It opens in new window">CrossRef 62. Testa, JR, Bellacosa, A (2001) AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A 98: pp. 10983-10985 10.1073/pnas.211430998" target="_blank" title="It opens in new window">CrossRef 63. Towbin, H, Staehelin, T, Gordon, J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 76: pp. 4350-4354 10.1073/pnas.76.9.4350" target="_blank" title="It opens in new window">CrossRef 64. Tu, WC, Wu, CC, Hsieh, HL, Chen, CY, Hsu, SL (2008) Honeybee venom induces calcium-dependent but caspase-independent apoptotic cell death in human melanoma A2058 cells. Toxicon 52: pp. 318-329 10.1016/j.toxicon.2008.06.007" target="_blank" title="It opens in new window">CrossRef 65. Hage, JA (2004) Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients. Br J Cancer 90: pp. 1543-1550 10.1038/sj.bjc.6601741" target="_blank" title="It opens in new window">CrossRef 66. Engeland, M, Nieland, LJ, Ramaekers, FC, Schutte, B, Reutelingsperger, CP (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31: pp. 1-9 10.1002/(SICI)1097-0320(19980101)31:1<1::AID-CYTO1>3.0.CO;2-R" target="_blank" title="It opens in new window">CrossRef 67. Wang, YQ, Cai, JY (2007) High-level expression of acidic partner-mediated antimicrobial peptide from tandem genes in Escherichia coli. Appl Biochem Biotechnol 141: pp. 203-213 10.1007/BF02729062" target="_blank" title="It opens in new window">CrossRef 68. Wang, NS, Unkila, MT, Reineks, EZ, Distelhorst, CW (2001) Transient expression of wild-type or mitochondrially targeted Bcl-2 induces apoptosis, whereas transient expression of endoplasmic reticulum-targeted Bcl-2 is protective against Bax-induced cell death. J Biol Chem 276: pp. 44117-44128 10.1074/jbc.M101958200" target="_blank" title="It opens in new window">CrossRef 69. Wang, C (2009) Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB. J Biol Chem 284: pp. 3804-3813 10.1074/jbc.M807191200" target="_blank" title="It opens in new window">CrossRef 70. Wendel, HG (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428: pp. 332-337 10.1038/nature02369" target="_blank" title="It opens in new window">CrossRef 71. Yang, ZL, Ke, YQ, Xu, RX, Peng, P (2007) Melittin inhibits proliferation and induces apoptosis of malignant human glioma cells. Nan Fang Yi Ke Da Xue Xue Bao 27: pp. 1775-1777 72. Yu, M, Wang, Y, Li, X, Fang, S, Xue, J, Song, J (2005) Synthesis of peptide fragment of melittin and the function of rheumatoid arthritis cure. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 22: pp. 1031-1035 73. Zhang, C, Li, B, Lu, SQ, Li, Y, Su, YH, Ling, CQ (2007) Effects of melittin on expressions of mitochondria membrane protein 7A6, cell apoptosis-related gene products Fas and Fas ligand in hepatocarcinoma cells. Zhong Xi Yi Jie He Xue Bao 5: pp. 559-563 10.3736/jcim20070517" target="_blank" title="It opens in new window">CrossRef
- 刊物主题:Biomedicine general; Pharmacy;
- 出版者:Springer Netherlands
- ISSN:2211-1069
文摘
Although melittin, a water-soluble 26-amino acid peptide derived from bee venom of Apis mellifera, is known to exert anti-proliferative effects on various tumor cell lines, very little is known about its potential molecular mechanism(s) of action. In the present study, we investigated the effects of melittin on the AKT/mTOR/S6K1/4E-BP1 activation, associated gene products, cellular proliferation, and apoptosis in several tumor cells. We found that melittin inhibited both constitutive phosphorylation of AKT and mTOR and exerted a significant time-dependent anti-proliferative effect on MM1.S cells as compared to other types of tumor cells. Indeed, melittin clearly suppressed the constitutive activation of AKT/mTOR/S6K1/4E-BP1 signaling cascades, which correlated with the induction of apoptosis. Melittin can cause broad-spectrum inhibition of AKT/mTOR/S6K1/4E-BP1 axes in multiple myeloma cells when compared with various pharmacological AKT/mTOR inhibitors. Aberrant AKT activation by pcDNA3-myr-HA-AKT1 plasmid could not prevent the observed suppressive effect of melittin on constitutive mTOR, S6K1, and 4E-BP1 activation and overexpression of Bcl-2 also attenuated melittin-mediated apoptosis in the cells. Our results clearly indicate that melittin can interfere with multiple signaling cascades involved in carcinogenesis and thereby used as a potential drug candidate for both the prevention and treatment of cancer.
| |
NGLC 2004-2010.National Geological Library of China All Rights Reserved.
Add:29 Xueyuan Rd,Haidian District,Beijing,PRC. Mail Add: 8324 mailbox 100083
For exchange or info please contact us via email.
| |