Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation

Cell Death Discovery
Yang FuFeng Zhu

Abstract

Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treating colon cancer in combination with chemotherapy drugs. This study was designed to explore whether dasatinib disturbed 5-Fu-triggered apoptosis in colon carcinoma. As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. Dasatinib dramatically decreased 5-Fu triggered apoptosis in colon carcinoma via suppression of Src activation. Our findings may have partially explained why dasatinib combined with FOLFOX failed to show a meaningful clinical response in mCRC.

References

Jan 1, 1993·The Journal of Clinical Investigation·M S TalamontiG E Gallick
Nov 13, 1998·Science·M H CardoneJ C Reed
Jun 7, 2003·Nature Cell Biology·Lindsey A AllanPaul R Clarke
Jul 30, 2003·Cancer Metastasis Reviews·Justin M Summy, Gary E Gallick
Jun 2, 2004·Nature Reviews. Cancer·Timothy J Yeatman
Jan 20, 2005·The Journal of Biological Chemistry·Deepak RainaDonald Kufe
Oct 6, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Faye M JohnsonNicholas J Donato
Mar 23, 2007·Nature Reviews. Molecular Cell Biology·Stefan J Riedl, Guy S Salvesen
May 1, 2007·Molecular Cell·Lindsey A Allan, Paul R Clarke
Apr 29, 2009·Cancer Letters·Jyoti NautiyalAdhip P N Majumdar
Oct 1, 2009·The FEBS Journal·Lindsey A Allan, Paul R Clarke
Oct 20, 2010·Oncogene·E F DunnD L Wheeler
Jan 14, 2011·Current Drug Targets·Antonio GnoniVito Lorusso
Jan 30, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Alfredo CarratoEric Van Cutsem
Feb 14, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·George SomloJavier Cortes
Jan 6, 2017·CA: a Cancer Journal for Clinicians·Rebecca L SiegelAhmedin Jemal
Feb 12, 2017·Trends in Cell Biology·Alexey V ZamaraevInna N Lavrik
Mar 11, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christine M ParseghianScott Kopetz

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Methods Mentioned

BETA
surgical resection
transfection
Assay
flow cytometry
ubiquitination
electrophoresis
FACS

Software Mentioned

ImageQuant
NetPhos
Simple
PEPTIDE
fect

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis