Skip to main content
SpringerLink
Log in

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

  • Research Article
  • Published:
Tumor Biology

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jaffer ZM, Chernoff J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol. 2002;34(7):713–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  25. Prestayko AW, D’Aoust JC, Issell BF, Crooke ST. Cisplatin (cis-diamminedichloroplatinum II). Cancer Treat Rev. 1979;6(1):17–39.

    Article  CAS  PubMed  Google Scholar 

  26. Galanski M. Recent developments in the field of anticancer platinum complexes. Recent patents on anti-cancer drug discovery. 2006;1(2):285–95.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

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

Author information

Authors and Affiliations

  1. Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, 221002, China

    Ding-Guo Zhang, Lin-Lin Mao, Jin-Xia Wu, Wen-Jia Cao, Jun-Nian Zheng & Dong-Sheng Pei

  2. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, China

    Jun-Nian Zheng

  3. LinYi People’s Hospital affiliated to Shandong University, 44 Wenhua Xi Road, Jinan, 250012, China

    Jinling Zhang

Authors
  1. Ding-Guo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin-Lin Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin-Xia Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Jia Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun-Nian Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dong-Sheng Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun-Nian Zheng or Dong-Sheng Pei.

Additional information

Ding-Guo Zhang and Jinling Zhang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, DG., Zhang, J., Mao, LL. et al. p21-Activated kinase 5 affects cisplatin-induced apoptosis and proliferation in hepatocellular carcinoma cells. Tumor Biol. 36, 3685–3691 (2015). https://doi.org/10.1007/s13277-014-3007-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-3007-5

Keywords

Search

Navigation