Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine.
Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapy. A few clinical trials have shown that the cytidine analogue gemcitabine appears to have antitumor activity for HCC, but the overall survival times remain to be improved. In this study, we examined the synergistic effect of adenovirus type 5 E1A (E1A) and gemcitabine on HCC and found that E1A sensitized J5, J7, Huh7, and HepG2 HCC cells to gemcitabine. To further study the E1A-mediated chemosensitization, we established stable cell lines that expressed the E1A gene and then examined whether E1A could have proapoptotic activity while expressed in HCC cells. Our results clearly showed that E1A sensitized HCC cells to gemcitabine through induction of apoptosis. To study the underlying mechanism, we tested nuclear factor (NF)-kappaB activity and found that NF-kappaB was activated in HCC cells treated with gemcitabine but not in HCC cells that expressed E1A. Occurrence of apoptosis entails cleavage of poly (ADP-ribose) polymerase (PARP), a nuclear protein involved in DNA repair, genome stability, and maintenance of telomere length. Our study showed that gemcitabine enhanced PARP expression. However, E1A did not induce PARP cleavage but rather suppressed PARP expression at the transcriptional level. Further study showed that both NF-kappaB and PARP played protective roles in the prevention of E1A+gemcitabine-induced apoptosis.
Lee
Wei-Ping
WP
Department of Internal Medicine and Cancer Center, Taipei Veterans General Hospital, 201 Shi-Pai Road Section 2, Taipei, Taiwan. wleemc@yahoo.com
Tai
Dar-In
DI
Tsai
Sun-Lung
SL
Yeh
Chau-Ting
CT
Chao
Yee
Y
Lee
Shou-Dong
SD
Hung
Mien-Chie
MC
D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000821:virology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000821:virology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000093542:Gemcitabine
D017500:Adenovirus E1A Proteins; D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003841:Deoxycytidine; D011065:Poly(ADP-ribose) Polymerases; D000093542:Gemcitabine