Resistance to cisplatin-induced apoptosis via PI3K-dependent survivin expression in a rat hepatoma cell line

Int J Oncol. 2010 Jul;37(1):89-96.


Hepatocellular carcinoma (HCC) is known to be resistant to chemotherapy. Survivin, a member of the inhibitor of apoptosis proteins, is overexpressed in most cancers but is absent in most normal adult tissue. The aim of this study was to investigate whether expression of survivin contributes to resistance to cisplatin-induced apoptosis. We confirmed induction of survivin expression in hepatoma in the N-diethylnitrosamine (DEN) induced rat and in the rat hepatoma cell line (K-251). We examined cell proliferation after treatment with cisplatin (CDDP) in the presence and absence of siRNA or the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 to suppress survivin or PI3K/Akt, respectively. Survivin was expressed in DEN-induced rat HCC with RT-PCR and Western blotting. Expression of survivin was observed primary in the nuclei and in the cytoplasm with immunohistochemistry. However, survivin was not detected in non-tumor tissues. Expression of survivin was also observed primarily in the nuclei and in the cytoplasm of the K-251 rat hepatoma cell line. CDDP induced survivin expression, which was blocked by siRNA. LY294002 also attenuated survivin expression induced by CDDP. Our results indicate that survivin expression via PI3K contributes to resistance to CDDP-induced apoptosis in a rat hepatoma cell line.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cells, Cultured
  • Cisplatin / pharmacology*
  • Diethylnitrosamine
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / genetics*
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / pathology
  • Male
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology*
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Survivin


  • Antineoplastic Agents
  • Birc5 protein, rat
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Survivin
  • Diethylnitrosamine
  • Phosphatidylinositol 3-Kinases
  • Cisplatin