Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways

Tsung Ying Yang, Gee Chen Chang, Kun Chieh Chen, Hsiao Wen Hung, Kuo Hsuan Hsu, Chi Hao Wu, Gwo Tarng Sheu, Shih Lan Hsu

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22 引文 斯高帕斯(Scopus)

摘要

Pemetrexed, a new-generation antifolate, has demonstrated promising single-agent activity in front- and second-line treatments of non-small cell lung cancer. However, the molecular mechanism of pemetrexed-mediated antitumor activity remains unclear. The current study shows that pemetrexed induced DNA damage and caspase-2, -3, -8, and -9 activation in A549 cells and that treatment with caspase inhibitors significantly abolished cell death, suggesting a caspase-dependent apoptotic mechanism. The molecular events of pemetrexed-mediated apoptosis was associated with the activation of ataxia telangiectasia mutated (ATM)/p53-dependent and -independent signaling pathways, which promoted intrinsic and extrinsic apoptosis by upregulating Bax, PUMA, Fas, DR4, and DR5 and activating the caspase signaling cascade. Supplementation with dTTP allowed normal S-phase progression and rescued apoptotic death in response to pemetrexed. Overall, our findings reveal that the decrease of thymidylate synthase and the increase of Bax, PUMA, Fas, DR4, and DR5 genes may serve as biomarkers for predicting responsiveness to pemetrexed.

原文英語
頁(從 - 到)183-194
頁數12
期刊Molecular Carcinogenesis
52
發行號3
DOIs
出版狀態已發佈 - 三月 1 2013
對外發佈

ASJC Scopus subject areas

  • 醫藥 (全部)

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