title: Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways.
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.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China.
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: Yang
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.forename: Kun-Chieh
authors.initials: KC
authors.lastname: Chen
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Hung
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Hsu
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Wu
authors.forename: Gwo-Tarng
authors.initials: GT
authors.lastname: Sheu
authors.forename: Shih-Lan
authors.initials: SL
authors.lastname: Hsu
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068437:Pemetrexed; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013942:Thymine Nucleotides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005971:Glutamates; D013942:Thymine Nucleotides; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000068437:Pemetrexed; D006147:Guanine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D020169:Caspases; C024157:thymidine 5'-triphosphate