Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine

Wei Ping Lee, Dar In Tai, Sun Lung Tsai, Chau Ting Yeh, Yee Chao, Shou Dong Lee, Mien-Chie Hung

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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)-κB activity and found that NF-κB 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-κB and PARP played protective roles in the prevention of E1A+gemcitabine-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)6229-6236
Number of pages8
JournalCancer Research
Volume63
Issue number19
StatePublished - Oct 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lee, W. P., Tai, D. I., Tsai, S. L., Yeh, C. T., Chao, Y., Lee, S. D., & Hung, M-C. (2003). Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine. Cancer Research, 63(19), 6229-6236.