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Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53‐dependent and ‐independent signaling pathways
Author(s) -
Yang TsungYing,
Chang GeeChen,
Chen KunChieh,
Hung HsiaoWen,
Hsu KuoHsuan,
Wu ChiHao,
Sheu GwoTarng,
Hsu ShihLan
Publication year - 2013
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.21842
Subject(s) - puma , pemetrexed , biology , apoptosis , thymidylate synthase , cancer research , caspase , programmed cell death , signal transduction , microbiology and biotechnology , cisplatin , cancer , genetics , chemotherapy , fluorouracil
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. © 2011 Wiley Periodicals, Inc.