title: Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer.
abstract: 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.
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland [3] Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: S-Q
authors.initials: SQ
authors.lastname: Liang
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland.
authors.forename: T M
authors.initials: TM
authors.lastname: Marti
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Dorn
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Froment
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland.
authors.forename: S R R
authors.initials: SR
authors.lastname: Hall
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Berezowska
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Kocher
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland.
authors.forename: R A
authors.initials: RA
authors.lastname: Schmid
authors.affiliation: 1] Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland [2] Department of Clinical Research, Thoracic Surgery Stem Cell Laboratory, University of Bern, Bern, Switzerland.
authors.forename: R-W
authors.initials: RW
authors.lastname: Peng
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005492:Folic Acid / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005492:Folic Acid