TY - JOUR
T1 - Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis
AU - Touil, Yasmine
AU - Igoudjil, Wassila
AU - Corvaisier, Matthieu
AU - Dessein, Anne Frederique
AU - Vandomme, Jerome
AU - Monte, Didier
AU - Stechly, Laurence
AU - Skrypek, Nicolas
AU - Langlois, Carole
AU - Grard, Georges
AU - Millet, Guillaume
AU - Leteurtre, Emmanuelle
AU - Dumont, Patrick
AU - Truant, Stephanie
AU - Pruvot, Francois Rene
AU - Hebbar, Mohamed
AU - Fan, Fan
AU - Ellis, Lee M.
AU - Formstecher, Pierre
AU - Van Seuningen, Isabelle
AU - Gespach, Christian
AU - Polakowska, Renata
AU - Huet, Guillemette
PY - 2014
Y1 - 2014
N2 - Purpose: Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. Results: We show that a clonal 5F31 cell population, resistant to 1 mmol/L 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FUfreemedium. Importantly, YES1 and YAP transcript levels were higher in livermetastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively). Conclusions: We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer.
AB - Purpose: Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. Results: We show that a clonal 5F31 cell population, resistant to 1 mmol/L 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FUfreemedium. Importantly, YES1 and YAP transcript levels were higher in livermetastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively). Conclusions: We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer.
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U2 - 10.1158/1078-0432.CCR-13-1854
DO - 10.1158/1078-0432.CCR-13-1854
M3 - Article
C2 - 24323901
AN - SCOPUS:84896713066
SN - 1078-0432
VL - 20
SP - 837
EP - 846
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -