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

doi:10.1002/mc.21842

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

Mol Carcinog. 2013 Mar;52(3):183-94. doi: 10.1002/mc.21842. Epub 2011 Nov 15.

Authors

Tsung-Ying Yang¹, Gee-Chen Chang, Kun-Chieh Chen, Hsiao-Wen Hung, Kuo-Hsuan Hsu, Chi-Hao Wu, Gwo-Tarng Sheu, Shih-Lan Hsu

Affiliation

¹ Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China.

PMID: 22086658
DOI: 10.1002/mc.21842

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimetabolites, Antineoplastic / pharmacology*
Apoptosis / drug effects*
Ataxia Telangiectasia Mutated Proteins
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Caspases / metabolism
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
DNA Damage / drug effects
DNA-Binding Proteins / metabolism*
Enzyme Activation / drug effects
Glutamates / pharmacology*
Guanine / analogs & derivatives*
Guanine / pharmacology
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Pemetrexed
Protein Serine-Threonine Kinases / metabolism*
S Phase Cell Cycle Checkpoints / drug effects
Signal Transduction / drug effects
Thymine Nucleotides / pharmacology
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins / metabolism*

Substances

Antimetabolites, Antineoplastic
Cell Cycle Proteins
DNA-Binding Proteins
Glutamates
Thymine Nucleotides
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Pemetrexed
Guanine
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Caspases
thymidine 5'-triphosphate