Insig2 is associated with colon tumorigenesis and inhibits Bax‐mediated apoptosis

Insulin‐induced gene 2 (Insig2) was recently identified as a putative positive prognostic biomarker for colon cancer prognosis. Insig2 has been previously reported to be an endoplasmic reticulum (ER) membrane protein, and a negative regulator of cholesterol synthesis. Here we report that Insig2 was...

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Published in:International journal of cancer 2008-07, Vol.123 (2), p.273-282
Main Authors: Li, Chang Gong, Gruidl, Mike, Eschrich, Steven, McCarthy, Susan, Wang, Hong‐Gang, Alexandrow, Mark G., Yeatman, Timothy J.
Format: Article
Language:English
Subjects:
apoptosis
Apoptosis - genetics
Bax
bcl-2-Associated X Protein - metabolism
Biological and medical sciences
biomarker
Biomarkers, Tumor - metabolism
Blotting, Western
Cell Line, Tumor
Colonic Neoplasms - genetics
Colonic Neoplasms - metabolism
Cytochromes c - metabolism
DNA, Complementary - chemical synthesis
Fluorescent Antibody Technique
Gene Expression Regulation, Neoplastic
Humans
Immunoprecipitation
Insig2
Intracellular Signaling Peptides and Proteins - metabolism
Kaplan-Meier Estimate
Medical sciences
Membrane Proteins - metabolism
Microscopy, Confocal
mitochondria
Mitochondria - metabolism
Polymerase Chain Reaction
Protein Array Analysis
RNA Interference
Tumors
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Summary:Insulin‐induced gene 2 (Insig2) was recently identified as a putative positive prognostic biomarker for colon cancer prognosis. Insig2 has been previously reported to be an endoplasmic reticulum (ER) membrane protein, and a negative regulator of cholesterol synthesis. Here we report that Insig2 was validated as a gene with univariate negative prognostic capacity to discriminate human colon cancer survivorship. To investigate the functional roles it plays in tumor development and malignancy, Insig2 was over‐expressed in colon cancer cells resulting in increased cellular proliferation, invasion, anchorage independent growth and inhibition of apoptosis. Over‐expression of Insig2 appeared to suppress chemotherapeutic drug treatment‐induced Bcl2 associated X protein (Bax) expression and activation. Insig2 was also found to localize to the mitochondria/heavy membrane fraction and associate with conformationally changed Bax. Moreover, Insig2 altered the expression of several additional apoptosis genes located in mitochondria, further supporting its new functional role in regulating mitochondrial mediated apoptosis. Our findings show that Insig2 is a novel colon cancer biomarker, and suggest, for the first time, a reasonable connection between Insig2 and Bax‐mediated apoptosis through the mitochondrial pathway. © 2008 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.23510