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

M. Mimeault, S. L. Johansson, S. K. Batra

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1079-1091
Number of pages13
JournalBritish journal of cancer
Volume108
Issue number5
DOIs
StatePublished - Mar 19 2013

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Keywords

  • chemoresistance
  • docetaxel
  • macrophage inhibitory cytokine-1
  • metastases
  • prostate cancer
  • targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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