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MK-2206 induces cell cycle arrest and apoptosis in HepG2 cells and sensitizes TRAIL-mediated cell death

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Abstract

It has become evident that AKT inhibitors have great potential in cancer treatment. In this study, we investigate the anticancer activity of MK-2206, a novel AKT inhibitor, on HepG2 hepatocellular carcinoma cell, and to show whether MK-2206 enhances the apoptosis-inducing potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The cell growth inhibition was evaluated by MTT assay and colony formation assay. Cell cycle distribution was assessed by propidium iodide flow cytometry. Apoptosis was determined by AnnexinV-FITC/PI double staining assay and caspase-9, casapse-7, caspase-3, and PARP cleavage. The results of present study showed that MK-2206-induced G1-phase arrest was associated with a marked decrease in the protein expression of cyclin D1 with concomitant induction of p21 and p27. MK-2206-induced apoptosis was characterized by cleavage of a pro-caspase in a concentration-dependent manner. Moreover, the MAP family kinases p38 kinase and JNK were activated by exposure to MK-2206. SB203580, an p38-specific inhibitor, partially blocked MK-2206-induced death of HepG2 cells and caspase activation. A combination of MK-2206 with TRAIL significantly inhibited growth of TRAIL resistant HepG2 cells. Taken together, our findings provide a new insight to better understand anticancer mechanisms of MK-2206, at least in HepG2 cell. Using of MK-2206 as a potent sensitizer to TRAIL-induced apoptotic cell death offers a promising means of enhancing the efficacy of TRAIL-based HCC treatments.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107

    Article  PubMed  Google Scholar 

  2. Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19(8):1893–1907. doi:10.1158/1055-9965

    Article  PubMed  Google Scholar 

  3. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365(12):1118–1127. doi:10.1056/NEJMra1001683

    Article  PubMed  CAS  Google Scholar 

  4. Carbajo-Pescador S, Steinmetz C, Kashyap A, Lorenz S, Mauriz JL, Heise M, Galle PR, González-Gallego J, Strand S (2013) Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells. Br J Cancer 108(2):442–449. doi:10.1038/bjc.2012.563

    Article  PubMed  CAS  Google Scholar 

  5. Altomare DA, Khaled AR (2012) Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem 19(22):3748–3762. doi:CMC-EPUB-20120607-24

    Article  PubMed  CAS  Google Scholar 

  6. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868. doi:S0092-8674(00)80595-4

    Article  PubMed  CAS  Google Scholar 

  7. Choudhury GG, Mahimainathan L, Das F, Venkatesan B, Ghosh-Choudhury N (2006) c-Src couples PI3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells. Cell Signal 18(11):1854–1864. doi:10.1016/j.cellsig.2006.02.003

    Article  PubMed  CAS  Google Scholar 

  8. Cheng GZ, Park S, Shu S, He L, Kong W, Zhang W, Yuan Z, Wang LH, Cheng JQ (2008) Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr Cancer Drug Targets 8(1):2–6

    Article  PubMed  CAS  Google Scholar 

  9. Osaki M, Oshimura M, Ito H (2004) PI3 K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9(6):667–676. doi:10.1023/B:APPT.0000045801.15585.dd

    Article  PubMed  CAS  Google Scholar 

  10. Lindsley CW (2010) The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update. Curr Top Med Chem 10(4):458–477

    Article  PubMed  CAS  Google Scholar 

  11. Cheng Y, Ren X, Zhang Y, Patel R, Sharma A, Wu H, Robertson GP, Yan L, Rubin E, Yang JM (2011) eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206. Cancer Res Cancer Res 71(7):2654–2663. doi:10.1158/0008-5472.CAN-10-2889

    Article  CAS  Google Scholar 

  12. Jin R, Nakada M, Teng L, Furuta T, Sabit H, Hayashi Y, Demuth T, Hirao A, Sato H, Zhao G, Hamada JI (2013) Combination therapy using notch and akt inhibitors is effective for suppressing invasion but not proliferation in glioma cells. Neurosci Lett 534:316–321. doi:10.1016/j.neulet.2012.12.008

    Article  PubMed  CAS  Google Scholar 

  13. Lan Y, Liu X, Zhang R, Wang K, Wang Y (2013) Hua ZC (2013) Lithium enhances TRAIL-induced apoptosis in human lung carcinoma A549 cells. Biometals. doi:10.1007/s10534-012-9607-x

    PubMed  Google Scholar 

  14. Carlisi D, D’Anneo A, Angileri L, Lauricella M, Emanuele S, Santulli A, Vento R, Tesoriere G (2011) Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J Cell Physiol 226(6):1632–1641. doi:10.1002/jcp.22494

    Article  PubMed  CAS  Google Scholar 

  15. Charette N, De Saeger C, Horsmans Y, Leclercq I, Stärkel P (2013) Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms. Cell Death Dis 4:e471. doi:10.1038/cddis.2012.200

    Article  PubMed  CAS  Google Scholar 

  16. Woo JS, Kim SM, Jeong CH, Ryu CH, Jeun SS (2013) Lipoxygenase inhibitor MK886 potentiates TRAIL-induced apoptosis through CHOP- and p38 MAPK-mediated up-regulation of death receptor 5 in malignant glioma. Biochem Biophys Res Commun 431(2):354–359. doi:10.1016/j.bbrc.2012.11.134

    Article  PubMed  CAS  Google Scholar 

  17. Wang S (2008) The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway. Oncogene 27(48):6207–6215. doi:10.1038/onc.2008.298

    Article  PubMed  CAS  Google Scholar 

  18. Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6(3):184–192. doi:10.1038/nrc1819

    Article  PubMed  CAS  Google Scholar 

  19. Jung KH, Zheng HM, Jeong Y, Choi MJ, Lee H, Hong SW, Lee HS, Son MK, Lee S, Hong S, Hong SS (2013) Suppression of tumor proliferation and angiogenesis of hepatocellular carcinoma by HS-104, a novel phosphoinositide 3-kinase inhibitor. Cancer Lett 328(1):176–187. doi:10.1016/j.canlet.2012.08.005

    Article  PubMed  CAS  Google Scholar 

  20. Somnay Y, Simon K, Harrison AD, Kunnimalaiyaan S, Chen H, Kunnimalaiyaan M (2013) Neuroendocrine phenotype alteration and growth suppression through apoptosis by MK-2206, an allosteric inhibitor of AKT, in carcinoid cell lines in vitro. Anticancer Drugs 24(1):66–72. doi:10.1097/CAD.0b013e3283584f75

    Article  PubMed  CAS  Google Scholar 

  21. Liu R, Liu D, Trink E, Bojdani E, Ning G, Xing M (2011) The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. J Clin Endocrinol Metab 96(4):E577–E585. doi:10.1210/jc.2010-2644

    Article  PubMed  CAS  Google Scholar 

  22. Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, Miller TW, Arteaga CL, Mills GB, Gonzalez-Angulo AM, Meric-Bernstam F (2012) Biomarkers of response to akt inhibitor MK-2206 in breast cancer. Clin Cancer Res 18(20):5816–5828. doi:10.1158/1078-0432.CCR-12-1141

    Article  PubMed  CAS  Google Scholar 

  23. Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H, Colvin R, Ding J, Tong L, Wu S, Hines J, Chen X (2012) A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 11(8):1672–1682. doi:10.1158/1535-7163.MCT-12-0131

    Article  PubMed  CAS  Google Scholar 

  24. Widmann C, Gibson S, Johnson GL (1998) Caspase-dependent cleavage of signaling proteins during apoptosis. A turn-off mechanism for anti-apoptotic signals. J Biol Chem 273(12):7141–7147

    Article  PubMed  CAS  Google Scholar 

  25. Chun J, Joo EJ, Kang M, Kim YS (2013) Platycodin D induces anoikis and caspase-mediated apoptosis via p38 MAPK in AGS human gastric cancer cells. Cell Biochem 114(2):456–470. doi:10.1002/jcb.24386

    Article  CAS  Google Scholar 

  26. Siegelin MD (2012) Utilization of the cellular stress response to sensitize cancer cells to TRAIL-mediated apoptosis. Expert Opin Ther Targets 16(8):801–817. doi:10.1517/14728222.2012.703655

    Article  PubMed  CAS  Google Scholar 

  27. Hellwig CT, Rehm M (2012) TRAIL signaling and synergy mechanisms used in TRAIL-based combination therapies. Mol Cancer Ther 11(1):3–13. doi:10.1158/1535-7163.MCT-11-0434

    Article  PubMed  CAS  Google Scholar 

  28. Maksimovic-Ivanic D, Stosic-Grujicic S, Nicoletti F, Mijatovic S (2012) Resistance to TRAIL and how to surmount it. Immunol Res 52(1–2):157–168. doi:10.1007/s12026-012-8284-8

    Article  PubMed  CAS  Google Scholar 

  29. Abou El Naga RN, Azab SS, El-Demerdash E, Shaarawy S, El-Merzabani M, Ammar el-SM (2013) Sensitization of TRAIL-induced apoptosis in human hepatocellular carcinoma HepG2 cells by phytochemicals. Life Sci 92(10):555–561. doi:10.1016/j.lfs.2013.01.017

    Article  PubMed  CAS  Google Scholar 

  30. Wang G, Wang X, Yu H, Wei S, Williams N, Holmes DL, Halfmann R, Naidoo J, Wang L, Li L, Chen S, Harran P, Lei X, Wang X (2013) Small-molecule activation of the TRAIL receptor DR5 in human cancer cells. Nat Chem Biol 9(2):84–89. doi:10.1038/nchembio.1153

    Article  PubMed  Google Scholar 

  31. Tazzari PL, Tabellini G, Ricci F, Papa V, Bortul R, Chiarini F, Evangelisti C, Martinelli G, Bontadini A, Cocco L, McCubrey JA, Martelli AM (2008) Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res 68(22):9394–9403. doi:10.1158/0008-5472.CAN-08-2815

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Grants from the National Natural Science Foundation of China (No. 81272683).

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Authors and Affiliations

  1. Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian, 271016, People’s Republic of China

    Peng Jiao

  2. Department of Radiation Oncology, Central Hospital of Taian, Taian, 271000, People’s Republic of China

    Yun-Sheng Zhou

  3. Shandong Institute of Pomology, Taian, 271000, People’s Republic of China

    Juan-Xia Yang

  4. School of Biological Science, Taishan Medical University, Chang Cheng Road, Taian, 271016, People’s Republic of China

    Ya-Li Zhao, Qiang-Qiang Liu, Chuang Yuan & Feng-Ze Wang

  5. Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Chang Cheng Road, Taian, 271016, People’s Republic of China

    Feng-Ze Wang

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  1. Peng Jiao
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Correspondence to Feng-Ze Wang.

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Jiao, P., Zhou, YS., Yang, JX. et al. MK-2206 induces cell cycle arrest and apoptosis in HepG2 cells and sensitizes TRAIL-mediated cell death. Mol Cell Biochem 382, 217–224 (2013). https://doi.org/10.1007/s11010-013-1737-0

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  • DOI: https://doi.org/10.1007/s11010-013-1737-0

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