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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Chemotherapy-Induced CXC-Chemokine/CXC-Chemokine Receptor Signaling in Metastatic Prostate Cancer Cells Confers Resistance to Oxaliplatin through Potentiation of Nuclear Factor-B Transcription and Evasion of Apoptosis

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom

Constitutive activation of nuclear factor (NF)-B is linked with the intrinsic resistance of androgen-independent prostate cancer (AIPC) to cytotoxic chemotherapy. Interleukin-8 (CXCL8) is a transcriptional target of NF-B whose expression is elevated in AIPC. This study sought to determine the significance of CXCL8 signaling in regulating the response of AIPC cells to oxaliplatin, a drug whose activity is reportedly sensitive to NF-B activity. Administration of oxaliplatin to PC3 and DU145 cells increased NF-B activity, promoting antiapoptotic gene transcription. In addition, oxaliplatin increased the transcription and secretion of CXCL8 and the related CXC-chemokine CXCL1 and increased the transcription and expression of CXC-chemokine receptors, especially CXC-chemokine receptor (CXCR) 2, which transduces the biological effects of CXCL8 and CXCL1. Stimulation of AIPC cells with CXCL8 potentiated NF-B activation in AIPC cells, increasing the transcription and expression of NF-B-regulated antiapoptotic genes of the Bcl-2 and IAP families. Coadministration of a CXCR2-selective antagonist, AZ10397767 (Bioorg Med Chem Lett 18:798–803, 2008), attenuated oxaliplatin-induced NF-B activation, increased oxaliplatin cytotoxicity, and potentiated oxaliplatin-induced apoptosis in AIPC cells. Pharmacological inhibition of NF-BorRNA interference-mediated suppression of Bcl-2 and survivin was also shown to sensitize AIPC cells to oxaliplatin. Our results further support NF-B activity as an important determinant of cancer cell sensitivity to oxaliplatin and identify the induction of autocrine CXCR2 signaling as a novel mode of resistance to this drug.

Address correspondence to: Dr. David Waugh, Centre for Cancer Research and Cell Biology, Queens University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. E-mail: d.waugh{at}qub.ac.uk