Marked improvement of cytotoxic effects induced by docetaxel on highly metastatic and androgen-independent prostate cancer cells by downregulating macrophage inhibitory cytokine-1.

Abstract

BACKGROUND:

Overexpression of macrophage inhibitory cytokine-1 (MIC-1) frequently occurs during the progression of prostate cancer (PC) to androgen-independent (AI) and metastatic disease states and is associated with a poor outcome of patients.

METHODS:

The gain- and loss-of-function analyses of MIC-1 were performed to establish its implications for aggressive and chemoresistant phenotypes of metastatic and AI PC cells and the benefit of its downregulation for reversing docetaxel resistance.

RESULTS:

The results have indicated that an enhanced level of secreted MIC-1 protein in PC3 cells is associated with their acquisition of epithelial-mesenchymal transition features and higher invasive capacity and docetaxel resistance. Importantly, the downregulation of MIC-1 in LNCaP-LN3 and PC3M-LN4 cells significantly decreased their invasive capacity and promoted the antiproliferative, anti-invasive and mitochrondrial- and caspase-dependent apoptotic effects induced by docetaxel. The downregulation of MIC-1 in PC3M-LN4 cells was also effective in promoting the cytotoxic effects induced by docetaxel on the side population (SP) endowed with stem cell-like properties and the non-SP cell fraction from PC3M-LN4 cells.

CONCLUSION:

These data suggest that the downregulation of MIC-1 may constitute a potential therapeutic strategy for improving the efficacy of current docetaxel-based chemotherapies, eradicating the total mass of PC cells and thereby preventing disease relapse and the death of PC patients.

• Authors: M Mimeault, S L Johansson, S K Batra
• Journal: British journal of cancer (Br J Cancer) Vol. 108 Issue 5 Pg. 1079-91 (Mar 19 2013) ISSN: 1532-1827 [Electronic] England
• PMID: 23449353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgen Antagonists
• Androgens
• Antineoplastic Agents
• Growth Differentiation Factor 15
• Taxoids
• Docetaxel

Topics

• Androgen Antagonists (therapeutic use)
• Androgens
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Docetaxel
• Down-Regulation
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition
• Growth Differentiation Factor 15 (genetics, metabolism)
• Humans
• Male
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Taxoids (pharmacology)