Resistance to cisplatin-induced apoptosis via PI3K-dependent survivin expression in a rat hepatoma cell line.
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.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Hiroyuki
H
Asechi
Etsuro
E
Hatano
Takashi
T
Nitta
Masaharu
M
Tada
Keiko
K
Iwaisako
Nobuyuki
N
Tamaki
Hiromitsu
H
Nagata
Masato
M
Narita
Atsuko
A
Yanagida
Iwao
I
Ikai
Shinji
S
Uemoto
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D004052:Diethylnitrosamine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077022:Survivin
D000970:Antineoplastic Agents; C516989:Birc5 protein, rat; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D004052:Diethylnitrosamine; D019869:Phosphatidylinositol 3-Kinases; D002945:Cisplatin