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Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung
S-Q Liang1, T M Marti2, P Dorn2
11] 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.
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.
Insights
Chemoresistance in non-small cell lung cancer (NSCLC) is linked to stem cell traits and epithelial-to-mesenchymal transition (EMT). Kaempferol inhibits EMT, restoring sensitivity to pemetrexed (MTA) chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Anticancer therapies often fail due to tumor resistance and recurrence.
- Chemoresistance in non-small cell lung cancer (NSCLC) remains a significant clinical challenge.
Purpose of the Study:
- To investigate the mechanisms underlying chemoresistance to pemetrexed (MTA) in NSCLC.
- To explore the role of epithelial-to-mesenchymal transition (EMT) in MTA chemoresistance.
- To evaluate kaempferol as a potential therapeutic agent to overcome MTA resistance.
Main Methods:
- Characterization of chemoresistant NSCLC cells for stem cell-like phenotypes.
- Induction and inhibition of EMT pathways in NSCLC models.
- Assessment of aldehyde dehydrogenase activity and clonogenic potential.
- Evaluation of kaempferol's effect on MTA sensitivity in chemoresistant cells.
Main Results:
- MTA chemoresistance in NSCLC is associated with stem cell-like properties and EMT activation.
- Experimental induction of EMT enhances chemoresistance to MTA.
- Kaempferol inhibits EMT signaling, rendering chemoresistant NSCLC cells sensitive to MTA.
- Elevated EMT signaling in primary human NSCLC cells correlates with MTA resistance, which is abrogated by kaempferol.
Conclusions:
- Epithelial-to-mesenchymal transition (EMT) activation is necessary and sufficient for chemoresistance to pemetrexed (MTA) in NSCLC.
- Kaempferol effectively reverses MTA chemoresistance by inhibiting the EMT pathway.
- Inhibiting EMT signaling presents a promising strategy to enhance chemotherapeutic responses in lung cancer.
