Journal article
CXCL12 Chemokine Expression and Secretion Regulates Colorectal Carcinoma Cell Anoikis through Bim-Mediated Intrinsic Apoptosis
PloS one, Vol.5(9), pp.1-12
09/22/2010
DOI: 10.1371/journal.pone.0012895
PMCID: PMC2943927
PMID: 20877573
Abstract
Background: Resistance to anoikis, apoptosis triggered by a loss of cellular adhesion to the underlying extracellular matrix, is a hallmark of metastatic cancer. Previously we have shown re-establishment of CXCL12 expression in colorectal carcinoma cells inhibits metastasis by enhancing anoikis sensitivity. The objective of these studies was to define the signaling mechanisms regulating CXCL12-mediated anoikis.
Methodology/Principal Findings: Adhesion, examined by crystal violet staining, immunofluorescence microscopy, and immunoblot analysis indicated decreased focal adhesion signaling corresponding with loss of adhesion in cells constitutively simulated by CXCL12. Loss of adhesion was inhibited by pertussis toxin treatment, indicating CXCL12 regulating anoikis through G(alpha i)-protein coupled receptors. Non-adherent HCT116 and HT29 colorectal carcinoma cells expressing CXCL12 exhibited enhanced anoikis sensitivity by propidium iodide staining, caspase activity assays, and immunoblot compared to GFP control cells. CXCL12 producing carcinomas cultured on poly-HEMA displayed heightened Bim and loss of Mcl-1 and Bcl-2 preceding cytochrome c release, and caspase-9 activation. RNAi knockdown of Bim reversed anoikis sensitivity of CXCL12-expressing cells and fostered increased soft-agar foci formation and hepatic tumors in an orthotopic mouse model of metastasis.
Conclusions/Significance: These data indicate CXCL12 provides a barrier to metastasis by increasing anoikis via activation of a Bim-mediated intrinsic apoptotic pathway. These results underscore the importance of retaining CXCL12 expression to sensitize colorectal carcinomas to anoikis and minimize tumor progression.
Details
- Title: Subtitle
- CXCL12 Chemokine Expression and Secretion Regulates Colorectal Carcinoma Cell Anoikis through Bim-Mediated Intrinsic Apoptosis
- Creators
- Luke J. Drury - Medical College of WisconsinMichael K. Wendt - Medical College of WisconsinMichael B. Dwinell - Medical College of Wisconsin
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.5(9), pp.1-12
- DOI
- 10.1371/journal.pone.0012895
- PMID
- 20877573
- PMCID
- PMC2943927
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library Science
- Number of pages
- 12
- Grant note
- R01DK062066 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Bobbie Nick Voss Charitable Foundation NIDDK 062066 / Medical College of Wisconsin Cancer Center
- Language
- English
- Date published
- 09/22/2010
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984459621102771
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