mda-7/IL-24 differentially regulates soluble and nuclear clusterin in prostate cancer.

Abstract

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a unique member of the IL-10 gene family, displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis, and modulation of anti-tumor immune responses. Here, we identify clusterin (CLU) as a MDA-7/IL-24 interacting protein in DU-145 cells and investigate the role of MDA-7/IL-24 in regulating CLU expression and mediating the antitumor properties of mda-7/IL-24 in prostate cancer. Ad.mda-7 decreased expression of soluble CLU (sCLU) and increased expression of nuclear CLU (nCLU). In the initial phase of Ad.mda-7 infection sCLU expression increased and CLU interacted with MDA-7/IL-24 producing a cytoprotective effect. Infection of stable clones of DU-145 prostate cancer cells expressing sCLU with Ad.mda-7 resulted in generation of nCLU that correlated with decreased cell viability and increased apoptosis. In the presence of mda-7/IL-24, sCLU-DU-145 cells displayed G(2)/M phase arrest followed by apoptosis. Similarly, Ad.mda-7 infection decreased cell migration by altering cytoskeleton in sCLU-DU-145 cells. Ad.mda-7-treated sCLU-DU-145 cells displayed a significant reduction in tumor growth in mouse xenograft models and reduced angiogenesis when compared to the vector control group. Tumor tissue lysates demonstrated enhanced nCLU generated from sCLU with increased apoptosis in the presence of MDA-7/IL-24. Our findings reveal novel aspects relative to the role of sCLU/nCLU in regulating the anticancer properties of MDA-7/IL-24 that may be exploited for developing enhanced therapies for prostate cancer.

• Authors: Sujit K Bhutia, Swadesh K Das, Timothy P Kegelman, Belal Azab, Rupesh Dash, Zhao-Zhong Su, Xiang-Yang Wang, Federica Rizzi, Saverio Bettuzzi, Seok-Geun Lee, Paul Dent, Steven Grant, David T Curiel, Devanand Sarkar, Paul B Fisher
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 227 Issue 5 Pg. 1805-13 (May 2012) ISSN: 1097-4652 [Electronic] United States
• PMID: 21732348 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Clusterin
• Interleukins
• interleukin-24

Topics

• Animals
• Cell Cycle (physiology)
• Cell Line, Tumor
• Cell Movement
• Cell Nucleus (metabolism)
• Clusterin (genetics, metabolism)
• Cytoskeleton (metabolism)
• Humans
• Interleukins (genetics, metabolism)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Prostatic Neoplasms (metabolism, pathology)
• Transplantation, Heterologous