Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells

Hiroshi Ariyama, Baoli Qin, Eishi Baba, Risa Tanaka, Kenji Mitsugi, Mine Harada, Shuji Nakano

研究成果: ジャーナルへの寄稿学術誌査読

58 被引用数 (Scopus)

抄録

Although gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been clinically demonstrated to be effective for certain cancer cell types, the molecular mechanisms of the anti-tumor activity have not been fully elucidated. In this study, we investigated the mechanism of gefitinib-induced growth inhibition and apoptosis in HAG-1 human gallbladder adenocarcinoma cells. Treatment of gefitinib at a dose of 1 μM resulted in a significant growth inhibition, and the cell number irreversibly declined after 72-h incubation, with a progressive expansion of apoptotic cell population over 120-h. Following 2-h treatment, gefitinib significantly inhibited EGFR autophosphorylation and subsequent downstream signaling pathway through Erk and Akt, and induced accumulation of cells in the G0/G1 phase of the cell cycle at 24-h, accompanied by a concomitant increase in p21 transcript and increased expression of p27. Gefitinib did not affect the amount of total and phosphorylated p53 at serine 15, but upregulated the expression of total Bax, with subsequent increase in p18 Bax, an active form of Bax. The expression of Bcl-2 and Bad was unchanged. An increase in gefitinib-induced expression of total Bax might be due to the decreased degradation of Bax, because the level of Bax mRNA has not been altered by gefitinib treatment. Gefitinib promoted the cleavage of full-length p21 Bax into p18 Bax in mitochondrial-enriched fraction, a characteristic feature of Bax activation toward apoptosis. Moreover, blockade of Bax by using anti-Bax small interfering double stranded RNA (siRNA) significantly reduced gefitinib-induced apoptosis. Taken together, these data suggest a critical role of p18 Bax in gefitinib-induced apoptosis.

本文言語英語
ページ(範囲)724-734
ページ数11
ジャーナルJournal of Cellular Biochemistry
97
4
DOI
出版ステータス出版済み - 3月 1 2006

!!!All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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