PMID- 24323901
OWN - NLM
STAT- MEDLINE
DCOM- 20141014
LR  - 20220409
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 20
IP  - 4
DP  - 2014 Feb 15
TI  - Colon cancer cells escape 5FU chemotherapy-induced cell death by entering 
      stemness and quiescence associated with the c-Yes/YAP axis.
PG  - 837-46
LID - 10.1158/1078-0432.CCR-13-1854 [doi]
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 mumol/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.
CI  - (c)2013 AACR
FAU - Touil, Yasmine
AU  - Touil Y
AD  - Authors' Affiliations: INSERM U837 Team 4 "Molecular and Cellular Targeting of 
      Cancers"; SIRIC ONCOLille; INSERM U837 Team 5 "Mucins, Epithelial 
      Differentiation, and Carcinogenesis" Jean-Pierre Aubert Research Centre, 
      Universite Lille and CHU, Univ Nord de France; Unit of Biostatistics; Department 
      of Digestive Surgery and Transplantation; Department of Medical Oncology, CHU, 
      Univ Nord de France; IBL UMR-8161 CNRS, Universite Lille Nord de France, Institut 
      Pasteur, Lille; IRI USR 3078 CNRS, Villeneuve d'Ascq; INSERM U938, Molecular and 
      Clinical Oncology, Hopital Saint Antoine, Universite Pierre et Marie Curie 6, 
      Paris, France; and The University of Texas MD Anderson Cancer Center, Houston, 
      Texas.
FAU - Igoudjil, Wassila
AU  - Igoudjil W
FAU - Corvaisier, Matthieu
AU  - Corvaisier M
FAU - Dessein, Anne-Frederique
AU  - Dessein AF
FAU - Vandomme, Jerome
AU  - Vandomme J
FAU - Monte, Didier
AU  - Monte D
FAU - Stechly, Laurence
AU  - Stechly L
FAU - Skrypek, Nicolas
AU  - Skrypek N
FAU - Langlois, Carole
AU  - Langlois C
FAU - Grard, Georges
AU  - Grard G
FAU - Millet, Guillaume
AU  - Millet G
FAU - Leteurtre, Emmanuelle
AU  - Leteurtre E
FAU - Dumont, Patrick
AU  - Dumont P
FAU - Truant, Stephanie
AU  - Truant S
FAU - Pruvot, Francois-Rene
AU  - Pruvot FR
FAU - Hebbar, Mohamed
AU  - Hebbar M
FAU - Fan, Fan
AU  - Fan F
FAU - Ellis, Lee M
AU  - Ellis LM
FAU - Formstecher, Pierre
AU  - Formstecher P
FAU - Van Seuningen, Isabelle
AU  - Van Seuningen I
FAU - Gespach, Christian
AU  - Gespach C
FAU - Polakowska, Renata
AU  - Polakowska R
FAU - Huet, Guillemette
AU  - Huet G
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131209
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (YY1AP1 protein, human)
RN  - EC 2.7.1.11 (Checkpoint Kinase 2)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins c-yes)
RN  - EC 2.7.10.2 (YES1 protein, human)
RN  - EC 2.7.11.1 (CHEK2 protein, human)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*pharmacology/therapeutic use
MH  - Biomarkers, Tumor/metabolism
MH  - Cell Cycle Checkpoints
MH  - Cell Cycle Proteins
MH  - Cell Nucleus/metabolism
MH  - Cell Proliferation
MH  - Checkpoint Kinase 2/metabolism
MH  - Chemotherapy, Adjuvant
MH  - Colonic Neoplasms/drug therapy/*metabolism/mortality/pathology
MH  - Disease-Free Survival
MH  - Drug Resistance, Neoplasm
MH  - Fluorouracil/*pharmacology/therapeutic use
MH  - Gene Expression
MH  - HT29 Cells
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Liver Neoplasms/drug therapy/*metabolism/mortality/secondary
MH  - Neoadjuvant Therapy
MH  - Neoplasm Micrometastasis/prevention & control
MH  - Neoplastic Stem Cells/drug effects/metabolism
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Proportional Hazards Models
MH  - Protein Transport
MH  - Proto-Oncogene Proteins c-yes/genetics/*metabolism
MH  - Transcription Factors/genetics/*metabolism
PMC - PMC4387277
MID - NIHMS671537
COIS- Disclosures: No potential conflicts of interest were disclosed.
EDAT- 2013/12/11 06:00
MHDA- 2014/10/15 06:00
PMCR- 2015/04/07
CRDT- 2013/12/11 06:00
PHST- 2013/12/11 06:00 [entrez]
PHST- 2013/12/11 06:00 [pubmed]
PHST- 2014/10/15 06:00 [medline]
PHST- 2015/04/07 00:00 [pmc-release]
AID - 1078-0432.CCR-13-1854 [pii]
AID - 10.1158/1078-0432.CCR-13-1854 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2014 Feb 15;20(4):837-46. doi: 10.1158/1078-0432.CCR-13-1854. 
      Epub 2013 Dec 9.