Article ; Online: Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis.
Clinical cancer research : an official journal of the American Association for Cancer Research
2013 Volume 20, Issue 4, Page(s) 837–846
Abstract: ... These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated ... Conclusions: We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells ...
| Abstract | 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 μmol/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 5FU-free medium. Importantly, YES1 and YAP transcript levels were higher in liver metastases 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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| MeSH term(s) | Antimetabolites, Antineoplastic/pharmacology ; Antimetabolites, Antineoplastic/therapeutic use ; Biomarkers, Tumor/metabolism ; Cell Cycle Checkpoints ; Cell Cycle Proteins ; Cell Nucleus/metabolism ; Cell Proliferation ; Checkpoint Kinase 2/metabolism ; Chemotherapy, Adjuvant ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/mortality ; Colonic Neoplasms/pathology ; Disease-Free Survival ; Drug Resistance, Neoplasm ; Fluorouracil/pharmacology ; Fluorouracil/therapeutic use ; Gene Expression ; HT29 Cells ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/mortality ; Liver Neoplasms/secondary ; Neoadjuvant Therapy ; Neoplasm Micrometastasis/prevention & control ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Proportional Hazards Models ; Protein Transport ; Proto-Oncogene Proteins c-yes/genetics ; Proto-Oncogene Proteins c-yes/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism |
| Chemical Substances | Antimetabolites, Antineoplastic ; Biomarkers, Tumor ; Cell Cycle Proteins ; Nuclear Proteins ; Transcription Factors ; YY1AP1 protein, human ; Checkpoint Kinase 2 (EC 2.7.1.11) ; Proto-Oncogene Proteins c-yes (EC 2.7.10.2) ; YES1 protein, human (EC 2.7.10.2) ; CHEK2 protein, human (EC 2.7.11.1) ; Fluorouracil (U3P01618RT) |
| Language | English |
| Publishing date | 2013-12-09 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1225457-5 |
| ISSN | 1557-3265 ; 1078-0432 |
| ISSN (online) | 1557-3265 |
| ISSN | 1078-0432 |
| DOI | 10.1158/1078-0432.CCR-13-1854 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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