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.
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.
Wilson
Catherine
C
Centre for Cancer Research and Cell Biology, Queens University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. d.waugh@qub.ac.uk.
Purcell
Colin
C
Seaton
Angela
A
Oladipo
Olabode
O
Maxwell
Pamela J
PJ
O'Sullivan
Joe M
JM
Wilson
Richard H
RH
Johnston
Patrick G
PG
Waugh
David J J
DJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D019898:Autocrine Communication; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D011471:Prostatic Neoplasms / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C508606:CXCL8 protein, human; D016209:Interleukin-8; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D023063:Receptors, Interleukin-8B; D000077150:Oxaliplatin