Expression of kinase-defective mutants of c-Src in human metastatic colon cancer cells decreases Bcl-xL and increases oxaliplatin- and Fas-induced apoptosis.
Authors
Griffiths, Gareth JKoh, Mei Yee
Brunton, Valerie G
Cawthorne, Christopher
Reeves, Natalie A
Greaves, Martin J
Tilby, Michael J
Pearson, D Graham
Ottley, Christopher J
Workman, Paul
Frame, Margaret C
Dive, Caroline
Affiliation
Cancer Research UK Paterson Institute for Cancer Research, Manchester, and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M20 4BX, UK.Issue Date
2004-10-29
Metadata
Show full item recordAbstract
Tumor resistance to current drugs prevents curative treatment of human colon cancer. A pressing need for effective, tumor-specific chemotherapies exists. The non-receptor-tyrosine kinase c-Src is overexpressed in >70% of human colon cancers and represents a tractable drug target. KM12L4A human metastatic colon cancer cells were stably transfected with two distinct kinase-defective mutants of c-src. Their response to oxaliplatin, to SN38, the active metabolite of irinotecan (drugs active in colon cancer), and to activation of the death receptor Fas was compared with vector control cells in terms of cell cycle arrest and apoptosis. Both kinase-defective forms of c-Src co-sensitized cells to apoptosis induced by oxaliplatin and Fas activation but not by SN38. Cells harboring kinase-defective forms of c-Src carrying function blocking point mutations in SH3 or SH2 domains were similarly sensitive to oxaliplatin, suggesting that reduction in kinase activity and not a Src SH2-SH3 scaffold function was responsible for the observed altered sensitivity. Oxaliplatin-induced apoptosis, potentiated by kinase-defective c-Src mutants, was dependent on activation of caspase 8 and associated with Bid cleavage. Each of the stable cell lines in which kinase-defective mutants of c-Src were expressed had reduced levels of Bcl-x(L.) However, inhibition of c-Src kinase activity by PP2 in vector control cells did not alter the oxaliplatin response over 72 h nor did it reduce Bcl-x(L) levels. The data suggest that longer term suppression of Src kinase activity may be required to lower Bcl-x(L) levels and sensitize colon cancer cells to oxaliplatin-induced apoptosis.Citation
Expression of kinase-defective mutants of c-Src in human metastatic colon cancer cells decreases Bcl-xL and increases oxaliplatin- and Fas-induced apoptosis. 2004, 279 (44):46113-21 J. Biol. Chem.Journal
The Journal of Biological ChemistryDOI
10.1074/jbc.M408550200PubMed ID
15326164Type
ArticleLanguage
enISSN
0021-9258ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M408550200
Scopus Count
Collections
Related articles
- Oxaliplatin sensitizes human colon cancer cells to TRAIL through JNK-dependent phosphorylation of Bcl-xL.
- Authors: El Fajoui Z, Toscano F, Jacquemin G, Abello J, Scoazec JY, Micheau O, Saurin JC
- Issue date: 2011 Aug
- Src activation regulates anoikis in human colon tumor cell lines.
- Authors: Windham TC, Parikh NU, Siwak DR, Summy JM, McConkey DJ, Kraker AJ, Gallick GE
- Issue date: 2002 Nov 7
- Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress.
- Authors: Kopetz S, Lesslie DP, Dallas NA, Park SI, Johnson M, Parikh NU, Kim MP, Abbruzzese JL, Ellis LM, Chandra J, Gallick GE
- Issue date: 2009 May 1
- Bcl-x(L) and Myeloid cell leukaemia-1 contribute to apoptosis resistance of colorectal cancer cells.
- Authors: Schulze-Bergkamen H, Ehrenberg R, Hickmann L, Vick B, Urbanik T, Schimanski CC, Berger MR, Schad A, Weber A, Heeger S, Galle PR, Moehler M
- Issue date: 2008 Jun 28
- Transforming growth factor-alpha prevents detachment-induced inhibition of c-Src kinase activity, Bcl-XL down-regulation, and apoptosis of intestinal epithelial cells.
- Authors: Rosen K, Coll ML, Li A, Filmus J
- Issue date: 2001 Oct 5