Abstract B200: Selective induction of CXCL8 signaling maintains viability in PTEN-depleted prostate cancer cells.

Abstract

Abstract Background: PTEN loss is associated with early prostate cancer progression. We sought to characterize whether PTEN loss regulates pro-inflammatory chemokine signaling and its functional significance to PTEN-depleted prostate cancer cells. Methods: Chemokine/chemokine receptor expression was assessed in vitro in established cell lines, exhibiting different levels of endogenous PTEN expression. Down-regulation of endogenous PTEN expression in DU145 and 22Rv1 cells was effected using transient siRNA or stable shRNA interventions. Chemokine expression was further evaluated by immunohistochemistry in prostate tissue from wild-type and PTEN+/− mice. Results: Loss of PTEN induced transcription-mediated increases in expression of CXCL8 and its receptors, CXCR1 and CXCR1 in DU145 and 22Rv1 cells. Stress-induced expression of CXCL8, CXCR1 and CXCR2 was greater in magnitude and duration in PTEN-null PC3 and LNCaP cells, in contrast to the dampened response observed in PTEN-expressing cells. PTEN loss had no effect on basal or stress-induced expression of CCL2, CXCL12 or their receptors CCR2 or CXCR4 in prostate cancer cells. The efficacy of CXCL8 signaling upon HIF-1 and NF-B transcription was also greater in magnitude and duration in PTEN-null prostate cancer cells or following siRNA-mediated PTEN knockdown. Increased expression of the orthologous murine chemokine KC was elevated in atypical cytological features of PTEN+/− prostate tissue relative to normal epithelium in PTENWT glands. Attenuation of CXCL8 signaling using siRNA oligonucleotides or shRNA vectors in cell-based models of partial or complete PTEN-loss significantly decreased cell viability. Furthermore, attenuation of CXCL8 signaling modulates the response of PTEN-depleted prostate cancer cells to clinically-relevant doses of ionizing radiation. Conclusion: PTEN loss promotes a selective up-regulation of CXCL8 signaling and increases the efficacy of CXCL8 signaling in prostate cancer cells. Functionally, this selective induction of CXCL8 signaling acts to maintain cell viability as an essential adaptation to the genetic instability arising from PTEN loss. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B200.