Tumor Biology

, Volume 36, Issue 5, pp 3685–3691 | Cite as

p21-Activated kinase 5 affects cisplatin-induced apoptosis and proliferation in hepatocellular carcinoma cells

Research Article

Abstract

p21-Activated kinase 5 (PAK5) is the last identified member of the PAK family. The PAKs are highly conserved serine/threonine and effector proteins for Cdc42 and Rac and are essential in regulating cell motility and survival. Previous studies have demonstrated that PAK5 played a pivotal role in apoptosis, proliferation, cancer migration, and invasion. However, the biological function of PAK5 in hepatocellular carcinoma, as well as its underlying mechanism, still remains to be fully elucidated. In the present study, we demonstrated that PAK5 markedly inhibited cisplatin-induced apoptosis and promoted cell proliferation in hepatocellular carcinoma cells. Moreover, our results showed that overexpression of PAK5 contributed to cell cycle regulation. In order to elucidate the underlying mechanism of PAK5 on cisplatin-induced apoptosis and cell cycle regulation, we also examined the protein expressions of chk2 and p-chk2. In summary, our study investigated the role of PAK5 in cisplatin-induced cellular processes and provided evidence of its underlying mechanism.

Keywords

p21-Activated kinase 5 Apoptosis Cell cycle arrest p-chk2 Cisplatin Hepatocellular carcinoma 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81372172) and the key project of the Education Department of China (212062) and the Science and Technology Department of Jiangsu Province (BK20130231, BK20141149).

Conflicts of interest

None

References

  1. 1.
    Jaffer ZM, Chernoff J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol. 2002;34(7):713–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Wen YY, Wang XX, Pei DS, Zheng JN. p21-Activated kinase 5: a pleiotropic kinase. Bioorg Med Chem Lett. 2013;23(24):6636–9. doi: 10.1016/j.bmcl.2013.10.051.CrossRefPubMedGoogle Scholar
  3. 3.
    Wang X, Gong W, Qing H, Geng Y, Wang X, Zhang Y, et al. P21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells. Tumour Biol. 2010;31(6):575–82. doi: 10.1007/s13277-010-0071-3.CrossRefPubMedGoogle Scholar
  4. 4.
    Pandey A, Dan I, Kristiansen TZ, Watanabe NM, Voldby J, Kajikawa E, et al. Cloning and characterization of PAK5, a novel member of mammalian p21-activated kinase-II subfamily that is predominantly expressed in brain. Oncogene. 2002;21(24):3939–48. doi: 10.1038/sj.onc.1205478.CrossRefPubMedGoogle Scholar
  5. 5.
    Dart AE, Wells CM. P21-activated kinase 4—not just one of the PAK. Eur J Cell Biol. 2013;92(4–5):129–38. doi: 10.1016/j.ejcb.2013.03.002.CrossRefPubMedGoogle Scholar
  6. 6.
    Dan C, Nath N, Liberto M, Minden A. PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells. Mol Cell Biol. 2002;22(2):567–77.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Han ZX, Wang XX, Zhang SN, Wu JX, Qian HY, Wen YY, et al. Downregulation of PAK5 inhibits glioma cell migration and invasion potentially through the PAK5-Egr1-MMP2 signaling pathway. Brain Tumor Pathol. 2013. doi: 10.1007/s10014-013-0161-1.PubMedGoogle Scholar
  8. 8.
    Gong W, An Z, Wang Y, Pan X, Fang W, Jiang B, et al. P21-activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration. Int J Cancer. 2009;125(3):548–55. doi: 10.1002/ijc.24428.CrossRefPubMedGoogle Scholar
  9. 9.
    Dummler B, Ohshiro K, Kumar R, Field J. Pak protein kinases and their role in cancer. Cancer Metastasis Rev. 2009;28(1–2):51–63. doi: 10.1007/s10555-008-9168-1.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cotteret S, Jaffer ZM, Beeser A, Chernoff J. p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol Cell Biol. 2003;23(16):5526–39.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wang XX, Cheng Q, Zhang SN, Qian HY, Wu JX, Tian H, et al. PAK5-Egr1-MMP2 signaling controls the migration and invasion in breast cancer cell. Tumour Biol. 2013;34(5):2721–9. doi: 10.1007/s13277-013-0824-x.CrossRefPubMedGoogle Scholar
  12. 12.
    Li D, Yao X, Zhang P. The overexpression of P21-activated kinase 5 (PAK5) promotes paclitaxel-chemoresistance of epithelial ovarian cancer. Mol Cell Biochem. 2013;383(1–2):191–9. doi: 10.1007/s11010-013-1767-7.CrossRefPubMedGoogle Scholar
  13. 13.
    D’Anzeo M, Faloppi L, Scartozzi M, Giampieri R, Bianconi M, Del Prete M, et al. The role of micro-RNAs in hepatocellular carcinoma: from molecular biology to treatment. Molecules. 2014;19(5):6393–406. doi: 10.3390/molecules19056393.CrossRefPubMedGoogle Scholar
  14. 14.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107.CrossRefPubMedGoogle Scholar
  15. 15.
    Poon RT, Fan ST, Lo CM, Ng IO, Liu CL, Lam CM, et al. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg. 2001;234(1):63–70.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chen HH, Kuo MT. Role of glutathione in the regulation of Cisplatin resistance in cancer chemotherapy. Met Based Drugs. 2010. doi:10.1155/2010/430939.Google Scholar
  17. 17.
    Shuck SC, Short EA, Turchi JJ. Eukaryotic nucleotide excision repair: from understanding mechanisms to influencing biology. Cell Res. 2008;18(1):64–72. doi: 10.1038/cr.2008.2.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Vitale I, Galluzzi L, Vivet S, Nanty L, Dessen P, Senovilla L, et al. Inhibition of Chk1 kills tetraploid tumor cells through a p53-dependent pathway. PLoS One. 2007;2(12):e1337. doi: 10.1371/journal.pone.0001337.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Brozovic A, Osmak M. Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett. 2007;251(1):1–16. doi: 10.1016/j.canlet.2006.10.007.CrossRefPubMedGoogle Scholar
  20. 20.
    Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16. doi: 10.1038/nrm1962.CrossRefPubMedGoogle Scholar
  21. 21.
    Li J, Wang Y, Song Y, Fu Z, Yu W. miR-27a regulates cisplatin resistance and metastasis by targeting RKIP in human lung adenocarcinoma cells. Mol Cancer. 2014;13(1):193. doi: 10.1186/1476-4598-13-193.
  22. 22.
    Unal OU, Yilmaz AU, Yavuzsen T, Akman T, Ellidokuz H. Intra-peritoneal cisplatin combined with intravenous paclitaxel in optimally debulked stage 3 ovarian cancer patients: an Izmir Oncology Group study. Asian Pac J Cancer Prev. 2014;15(15):6165–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Liang X, Reed E, Yu JJ. Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells. Int J Mol Med. 2006;17(5):703–8.PubMedGoogle Scholar
  24. 24.
    Pabla N, Huang S, Mi QS, Daniel R, Dong Z. ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J Biol Chem. 2008;283(10):6572–83. doi: 10.1074/jbc.M707568200.CrossRefPubMedGoogle Scholar
  25. 25.
    Prestayko AW, D’Aoust JC, Issell BF, Crooke ST. Cisplatin (cis-diamminedichloroplatinum II). Cancer Treat Rev. 1979;6(1):17–39.CrossRefPubMedGoogle Scholar
  26. 26.
    Galanski M. Recent developments in the field of anticancer platinum complexes. Recent patents on anti-cancer drug discovery. 2006;1(2):285–95.CrossRefPubMedGoogle Scholar
  27. 27.
    Cotteret S, Chernoff J. Nucleocytoplasmic shuttling of Pak5 regulates its antiapoptotic properties. Mol Cell Biol. 2006;26(8):3215–30. doi: 10.1128/MCB. 26.8.3215-3230.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Fang ZP, Jiang BG, Gu XF, Zhao B, Ge RL, Zhang FB. P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma. Acta Pharmacol Sin. 2014;35(1):82–8. doi: 10.1038/aps.2013.31.CrossRefPubMedGoogle Scholar
  29. 29.
    Gu J, Li K, Li M, Wu X, Zhang L, Ding Q, et al. A role for p21-activated kinase 7 in the development of gastric cancer. FEBS J. 2013;280(1):46–55. doi: 10.1111/febs.12048.CrossRefPubMedGoogle Scholar
  30. 30.
    Zcharia E, Atzmon R, Nagler A, Shimoni A, Peretz T, Vlodavsky I, et al. Inhibition of matrix metalloproteinase-2 by halofuginone is mediated by the Egr1 transcription factor. Anticancer Drugs. 2012;23(10):1022–31. doi: 10.1097/CAD.0b013e328357d186.CrossRefPubMedGoogle Scholar
  31. 31.
    Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22(47):7265–79. doi: 10.1038/sj.onc.1206933.CrossRefPubMedGoogle Scholar
  32. 32.
    Damia G, Filiberti L, Vikhanskaya F, Carrassa L, Taya Y, D’Incalci M, et al. Cisplatinum and taxol induce different patterns of p53 phosphorylation. Neoplasia. 2001;3(1):10–6. doi: 10.1038/sj/neo/7900122.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Antoni L, Sodha N, Collins I, Garrett MD. CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nat Rev Cancer. 2007;7(12):925–36. doi: 10.1038/nrc2251.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Ding-Guo Zhang
    • 1
  • Jinling Zhang
    • 3
  • Lin-Lin Mao
    • 1
  • Jin-Xia Wu
    • 1
  • Wen-Jia Cao
    • 1
  • Jun-Nian Zheng
    • 1
    • 2
  • Dong-Sheng Pei
    • 1
  1. 1.Jiangsu Key Laboratory of Biological Cancer TherapyXuzhou Medical CollegeXuzhouChina
  2. 2.Center of Clinical OncologyAffiliated Hospital of Xuzhou Medical CollegeXuzhouChina
  3. 3.LinYi People’s Hospital affiliated to Shandong UniversityJinanChina

Personalised recommendations