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 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)183-194
Number of pages12
JournalMolecular Carcinogenesis
Issue number3
Publication statusPublished - Mar 1 2013
Externally publishedYes


ASJC Scopus subject areas

  • Medicine(all)

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