CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity

David Z. Qian, Brooks L.S. Rademacher, Janet Pittsenbarger, Chung Ying Huang, Anne Myrthue, Celestia S. Higano, Mark Garzotto, Peter S. Nelson, Tomasz M. Beer

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

BACKGROUND. Metastatic prostate cancer is either inherently resistant to chemotherapy or rapidly acquires this phenotype after chemotherapy exposure. In this study, we identified a docetaxel-induced resistance mechanism centered on CCL2. METHODS. We compared the gene expression profiles in individual human prostate cancer specimens before and after exposure to chemotherapy collected from previously untreated patients who participated in a clinical trial of preoperative chemotherapy. Subsequently, we used the gain- and loss-of-function approach in vitro to identify a potential mechanism underlying chemotherapy resistance. RESULTS. Among the molecular signatures associated with treatment, several genes that regulate the inflammatory response and chemokine activity were upregulated including a significant increase in transcripts encoding the CCchemokine CCL2. Docetaxel increased CCL2 expression in prostate cancer cell lines in vitro. CCL2-specific siRNA inhibited LNCaP and LAPC4 cell proliferation and enhanced the growth inhibitory effect of low-dose docetaxel. In contrast, overexpression of CCL2 or recombinant CCL2 protein stimulated prostate cancer cell proliferation and rescued cells from docetaxel-induced cytotoxicity. This protective effect of CCL2 was associated with activation of the ERK/MAP kinase and PI3K/AKT, inhibition of docetaxel-induced Bcl2 phosphorylation at serine 70, phosphorylation of Bad, and activation of caspase-3. The addition of a PI3K/AKT inhibitor Ly294002 reversed the CCL2 protection and was additive to docetaxel-induced toxicity. CONCLUSION. These results support a mechanism of chemotherapy resistance mediated by cellular stress responses involving the induction of CCL2 expression and suggest that inhibiting CCL2 activity could enhance therapeutic responses to taxane-based therapy.

Original languageEnglish (US)
Pages (from-to)433-442
Number of pages10
JournalProstate
Volume70
Issue number4
DOIs
StatePublished - Mar 1 2010

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Keywords

  • CCL2
  • Chemotherapy resistance
  • Inflammation
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Qian, D. Z., Rademacher, B. L. S., Pittsenbarger, J., Huang, C. Y., Myrthue, A., Higano, C. S., Garzotto, M., Nelson, P. S., & Beer, T. M. (2010). CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity. Prostate, 70(4), 433-442. https://doi.org/10.1002/pros.21077