Relevance of pro-angiogenic signalling as a mode of relapse to anti-androgen therapy in prostate cancer

• Main Author: Mckechnie, Melanie
• Published: Queen's University Belfast 2013
• Subjects: 616.129
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.602503

Administration of bicalutamide to LNCaP tumours induces a rapid and sustained hypoxia in the prostate. This treatment-induced hypoxia (> 14 days) promotes an increased synthesis of the CXC-chemokine Interleukin-8(CXCL8) co-incident with increasing oxygen tension and the restoration of tumour vascularisation. Consequently, the hypothesis under investigation was that hypoxia-induced CXCL8 signalling underpins resistance to bicalutamide-treated tumours and facilitates the adoption of more aggressive cancer cells. Culturing of22Rvl and cells under hypoxic conditions (mimicking the microenvironment effects resulting from bicalutamide treatment) increased the transcriptional activity of the AR, HIF-Ia and NF-KB, inducing expression of downstream target genes, associated with survival, metabolic adaptation and angiogenesis. The magnitude and duration of these increases was greater in LNCaP cells. Administration of bicalutamide or siRNA-mediated down-regulation of the AR failed to reduce expression of pro-angiogenic, pro-survival and metabolism-associated genes. However, concurrent knockdown of both HIF-Ia and NF-KB activity using gene-targeted siRNAs resulted in an effective repression of these hypoxia-induced disease-progressing genes. Expression of CXCL8 and its receptors, CXCRl and CXCR2, was also up-regulated in particularly in hypoxic LNCaP cells. CXCL8 signalling was shown to underpin hypoxiainduced AR, HIF -1 and NF-KB transcription in hypoxic LNCaP cell s, up-regulating genes associated with survival and metabolic adaptation. We have previously shown that HIF-l and NF-KB activity underpin the transcription of the CXCRI and CXCR2 receptors, suggesting that either suppression of the TFs or targeting of the CXCR1I2 receptors may provide strategies to enhance anti-tumour responses in hypoxic prostate cancer cells. The proteasome inhibitor Bortezomib was shown to attenuate hypoxia-induced AR- and HIF-l- activation but failed to reduce NF -KB activity. Instead, a direct targeting of CXCL8 signalling increased the sensitivity of LNCaP cells to bilcalutamide, and repressed hypoxia-induced transcription and expression of disease-promoting genes. Targeting CXCL8 signalling may therefore be a relevant strategy to enhance tumour response to anti-androgen strategies .