Abstract B162: Differential stress‐induced CXC‐chemokine expression, signaling and responses in PTEN‐deficient prostate tumors Free

We have shown that expression of the proinflammatory CXC chemokine, interleukin‐8 (IL‐8) and its receptors CXCR1 and CXCR2 is elevated in malignant prostate cancer (CaP) epithelium. Published studies confirm that hypoxia and/or chemotherapy‐induced stresses underpin AP‐1, HIF‐1 and NFκB‐mediated transcription‐driven increases in IL‐8, CXCR1 and CXCR2 expression in CaP cells. The current study determines the relevance of PTEN, a commonly mutated or deleted tumor suppressor gene in CaP, in regulating the induction of CXC‐chemokine signaling and the cellular response of stressed CaP cells. Time‐dependent increases in CXCL8, CXCR1 and CXCR2 mRNA were observed in PTEN‐deficient LNCaP and PC3 cells. ELISA confirmed increased IL‐8 secretion following hypoxia, while immunoblotting confirmed elevated CXCR1 and CXCR2 expression in both cells. In contrast, CXCL8, CXCR1 and CXCR2 expression was only marginally up‐regulated in PTEN wild‐type DU145 and 22Rv1 cells under hypoxia. Subsequently, PTEN status was shown to regulate the magnitude and duration of CXC‐chemokine‐promoted signaling and altered gene expression profiles. For example, CXCL8 administration increased expression of HIF‐α and increased the activity of this transcription factor in PTEN‐deficient LNCaP and PC3 cells but not in PTEN wild‐type cells. Furthermore, expression of HIF‐1 target genes (VEGF, TGF) was also induced following CXCL8 stimulation in PTEN deficient but not PTEN wild‐type cells. Attenuation of PTEN in the DU145 and 22Rv1 cells using siRNA revealed the CXCL8‐induced responses including the increase in HIF‐1 expression and activation. Functionally, the transcription‐mediated elevation in IL‐8 signalling underpins an increased survival of hypoxic prostate cancer cells to DNA‐damage‐based chemotherapy. Additionally, CXCL8 signaling was shown to induce cysteine cathepsin and serine protease expression in CaP cell lines and stromal cells, indicating a capacity to promote tumor invasion. In summary, our studies suggest that the magnitude of CXC‐chemokine signaling and its subsequent effects are enhanced in PTEN‐deficient prostate tumors, promoting proliferation, survival, chemoresistance, androgen‐independent transition and changes in the tumor microenvironment.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B162.