Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer

• Published in: Cell death & disease Vol. 6; no. 7; p. e1824
• Main Authors: Liang, S-Q, Marti, T M, Dorn, P, Froment, L, Hall, S R R, Berezowska, S, Kocher, G, Schmid, R A, Peng, R-W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.07.2015; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 38/39; 38/77; 631/80/84/2176; 692/699/67/1059/2326; 692/699/67/1059/99; 692/699/67/1612; 82/1; 82/80; 96; Antibodies; Antineoplastic Agents - administration & dosage; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Folic Acid - metabolism; Folic Acid Antagonists - administration & dosage; Humans; Immunology; Life Sciences; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Original; original-article; Signal Transduction
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.195

Anticancer therapies currently used in the clinic often can neither eradicate the tumor nor prevent disease recurrence due to tumor resistance. In this study, we showed that chemoresistance to pemetrexed, a multi-target anti-folate (MTA) chemotherapeutic agent for non-small cell lung cancer (NSCLC), is associated with a stem cell-like phenotype characterized by an enriched stem cell gene signature, augmented aldehyde dehydrogenase activity and greater clonogenic potential. Mechanistically, chemoresistance to MTA requires activation of epithelial-to-mesenchymal transition (EMT) pathway in that an experimentally induced EMT per se promotes chemoresistance in NSCLC and inhibition of EMT signaling by kaempferol renders the otherwise chemoresistant cancer cells susceptible to MTA. Relevant to the clinical setting, human primary NSCLC cells with an elevated EMT signaling feature a significantly enhanced potential to resist MTA, whereas concomitant administration of kaempferol abrogates MTA chemoresistance, regardless of whether it is due to an intrinsic or induced activation of the EMT pathway. Collectively, our findings reveal that a bona fide activation of EMT pathway is required and sufficient for chemoresistance to MTA and that kaempferol potently regresses this chemotherapy refractory phenotype, highlighting the potential of EMT pathway inhibition to enhance chemotherapeutic response of lung cancer.