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.

Low folate metabolic stress reprograms DNA methylation‐activated sonic hedgehog signaling to mediate cancer stem cell‐like signatures and invasive tumour stage‐specific malignancy of human colorectal cancers

“…In concordance with recent advances in CSC malignancy development as cancer stem cell diseases, 2 the present study provides several first lines of evidence to signify the LFMS-induced CSC-like potentials of human CRC tissues and cells: (1) induced transcript and protein expressions of the pluripotent-associated Shh signaling markers; (2) activated trans-differentiation by regulation of EMT markers; (3) induced expressions of the pluripotent CSC markers (SOX2, OCT4 and NANOG); (4) increased MMP2/MMP9 enzymatic digestion on matrix protein for invasion; (5) promoted CSC self-renewal capability of anchorage-independent tumor-spheroid formation. LFMSinduced CSC-like potentials of human CRC was consistent with few studies on the xenograft mouse model of liver cancers, 30 antifolate-treated non-small cell lung cancers 31 and colonic cancers. 32 In line with the robust activation of the Shh-Gli pathway required for expressing stemness potentials in different cancer contexts, 7-12 blockage of FD-activated Shh signaling by CYC abolished FD-promoted SOX2 gene expression, EMT trans-differentiation, oncosphere formation and subsequently abrogated FD-enhanced invasion of human adenocarcinoma cells.…”

Cisplatin resistance in gastric cancer cells is involved with GPR30‐mediated epithelial‐mesenchymal transition

“…These findings indicate that the formation of cisplatin resistance is associated with EMT. Numerous studies have shown that EMT plays an important role in the progression, invasion, metastasis and drug resistance of a variety of cancers including GC . In this study, E‐cadherin expression was down‐regulated and vimentin expression was up‐regulated in GC cells treated with cisplatin, indicating that GC cells treated with cisplatin experienced EMT‐like changes.…”

“…Epithelial-mesenchymal transition (EMT) is one of the most widely studied mechanisms not only in GC 9 but also in pancreatic cancer, 10 breast cancer, 11 and lung cancer. 12 EMT is a reversible process in which epithelial cells lose polarity and cell-cell adhesion characteristics and acquire mesenchymal cell characteristics. 13 EMTexpressing cancer cells showed decreased expression of epithelial cell markers such as E-cadherin and ZO-1, while expression of mesenchymal cell markers such as vimentin and N-cadherin increased.…”

Epithelial–mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease

“…Particularly in NSCLC, EMT phenotype correlates with drug resistance, mutations of EGFR (epidermal growth factor receptor), and formation of cancer stem cells (CSCs) characterized by an enriched stem cell signature and a heightened tumorigenic potential (Bartis et al, ). EMT can drive resistance to multi‐targeted anti‐folate chemotherapy (Liang et al, ) as well as to EGFR inhibition (Thomson et al, ); NSCLC lines in a mesenchymal state were insensitive to growth arrest effect of EGFR inhibition both in vitro and in xenografts (Thomson et al, ). Furthermore, the gefitinib‐resistant subline of A549 (A549/GR) exhibited a spindle‐shape morphology and higher levels of mesenchymal marker vimentin with concomitant decrease in CDH1, suggesting an EMT (Rho et al, ).…”