Chemotherapy-induced CXC-chemokine/CXC-chemokine receptor signaling in metastatic prostate cancer cells confers resistance to oxaliplatin through potentiation of nuclear factor-kappaB transcription and evasion of apoptosis

• Published in: The Journal of pharmacology and experimental therapeutics 2008-12, Vol.327 (3), p.746-759
• Main Authors: Wilson, Catherine, Purcell, Colin, Seaton, Angela, Oladipo, Olabode, Maxwell, Pamela J, O'Sullivan, Joe M, Wilson, Richard H, Johnston, Patrick G, Waugh, David J J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Autocrine Communication; Cell Line; Drug Resistance, Neoplasm; Humans; Interleukin-8 - genetics; Interleukin-8 - physiology; Male; Neoplasm Metastasis; NF-kappa B - metabolism; Organoplatinum Compounds - pharmacology; Oxaliplatin; Prostatic Neoplasms - pathology; Receptors, Interleukin-8B - antagonists & inhibitors; Receptors, Interleukin-8B - physiology; Signal Transduction; Transcription, Genetic
• ISSN: 1521-0103
• DOI: 10.1124/jpet.108.143826

Constitutive activation of nuclear factor (NF)-kappaB is linked with the intrinsic resistance of androgen-independent prostate cancer (AIPC) to cytotoxic chemotherapy. Interleukin-8 (CXCL8) is a transcriptional target of NF-kappaB 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-kappaB activity. Administration of oxaliplatin to PC3 and DU145 cells increased NF-kappaB 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-kappaB activation in AIPC cells, increasing the transcription and expression of NF-kappaB-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-kappaB activation, increased oxaliplatin cytotoxicity, and potentiated oxaliplatin-induced apoptosis in AIPC cells. Pharmacological inhibition of NF-kappaBorRNA interference-mediated suppression of Bcl-2 and survivin was also shown to sensitize AIPC cells to oxaliplatin. Our results further support NF-kappaB 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.