The ERK-ZEB1 pathway mediates epithelial-mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids.
High thymidylate synthase (TS) level in cancer tissue is considered to result in resistance to pemetrexed therapy for advanced stages of nonsquamous non-small cell lung cancers. To further investigate the mechanism of pemetrexed resistance and potential prognostic outcomes in lung cancer, we established pemetrexed-resistant lung adenocarcinoma cell sublines from CL1 harboring a mutated TP53 gene (R248W) and A549 harboring wild-type TP53. We found the TS expression is upregulated in both pemetrexed-resistant sublines and the reduced TS level achieved through shRNA inhibition resulted in higher pemetrexed sensitivity. We also demonstrated that the acquisitions of pemetrexed resistance enhances epithelial-mesenchymal transition (EMT) in vivo with a mice animal model and in vitro with CL1 and A549 sublines, which was associated with upregulation of ZEB1 which, in turn, downregulates E-cadherin and upregulates fibronectin. When ERK1/2 phosphorylation was reduced by an inhibitor (U0126) or siRNA inhibition, both pemetrexed-resistant sublines reduced their migration and invasion abilities. Therefore, the ERK-mediated pathways induce apoptosis with pemetrexed treatment, and may in turn mediate EMT when cancer cells are resistant to pemetrexed. We further demonstrated that the growth of pemetrexed-resistant tumors could be inhibited by vinblastine in vivo and vincristine in vitro. Our data indicate that pemetrexed resistance could be relieved by non-cross-resistant chemotherapeutic drugs such as vinca alkaloids and might be independent to TP53 status. Furthermore, the phosphorylation of ERK was reduced by vincristine. This finding provides a new insight for overcoming pemetrexed resistance and metastasis by application of vinca alkaloids.
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
L-Y
LY
Chiu
Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan.
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IL
Hsin
Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
T-Y
TY
Yang
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan.|Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
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WW
Sung
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
J-Y
JY
Chi
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
J T
JT
Chang
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
J-L
JL
Ko
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
G-T
GT
Sheu
D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D000068437:Pemetrexed / Q000494:pharmacology; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014748:Vinca Alkaloids / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014748:Vinca Alkaloids; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000068437:Pemetrexed