PMID- 22939387 OWN - NLM STAT- MEDLINE DCOM- 20140207 LR - 20220309 IS - 1873-7560 (Electronic) IS - 0302-2838 (Print) IS - 0302-2838 (Linking) VI - 64 IP - 2 DP - 2013 Aug TI - Potentiation of inflammatory CXCL8 signalling sustains cell survival in PTEN-deficient prostate carcinoma. PG - 177-88 LID - S0302-2838(12)00967-0 [pii] LID - 10.1016/j.eururo.2012.08.032 [doi] AB - BACKGROUND: Inflammation and genetic instability are enabling characteristics of prostate carcinoma (PCa). Inactivation of the tumour suppressor gene phosphatase and tensin homolog (PTEN) is prevalent in early PCa. The relationship of PTEN deficiency to inflammatory signalling remains to be characterised. OBJECTIVE: To determine how loss of PTEN functionality modulates expression and efficacy of clinically relevant, proinflammatory chemokines in PCa. DESIGN, SETTING, AND PARTICIPANTS: Experiments were performed in established cell-based PCa models, supported by pathologic analysis of chemokine expression in prostate tissue harvested from PTEN heterozygous (Pten(+/-)) mice harbouring inactivation of one PTEN allele. INTERVENTIONS: Small interfering RNA (siRNA)- or small hairpin RNA (shRNA)-directed strategies were used to repress PTEN expression and resultant interleukin-8 (CXCL8) signalling, determined under normal and hypoxic culture conditions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Changes in chemokine expression in PCa cells and tissue were analysed by real-time polymerase chain reaction (PCR), immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry; effects of chemokine signalling on cell function were assessed by cell cycle analysis, apoptosis, and survival assays. RESULTS AND LIMITATIONS: Transient (siRNA) or prolonged (shRNA) PTEN repression increased expression of CXCL8 and its receptors, chemokine (C-X-C motif) receptor (CXCR) 1 and CXCR2, in PCa cells. Hypoxia-induced increases in CXCL8, CXCR1, and CXCR2 expression were greater in magnitude and duration in PTEN-depleted cells. Autocrine CXCL8 signalling was more efficacious in PTEN-depleted cells, inducing hypoxia-inducible factor-1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) transcription and regulating genes involved in survival and angiogenesis. Increased expression of the orthologous chemokine KC was observed in regions displaying atypical cytologic features in Pten(+/-) murine prostate tissue relative to normal epithelium in wild-type PTEN (Pten(WT)) glands. Attenuation of CXCL8 signalling decreased viability of PCa cells harbouring partial or complete PTEN loss through promotion of G1 cell cycle arrest and apoptosis. The current absence of clinical validation is a limitation of the study. CONCLUSIONS: PTEN loss induces a selective upregulation of CXCL8 signalling that sustains the growth and survival of PTEN-deficient prostate epithelium. CI - Copyright (c) 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. FAU - Maxwell, Pamela J AU - Maxwell PJ AD - Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland. FAU - Coulter, Jonathan AU - Coulter J FAU - Walker, Steven M AU - Walker SM FAU - McKechnie, Melanie AU - McKechnie M FAU - Neisen, Jessica AU - Neisen J FAU - McCabe, Nuala AU - McCabe N FAU - Kennedy, Richard D AU - Kennedy RD FAU - Salto-Tellez, Manuel AU - Salto-Tellez M FAU - Albanese, Chris AU - Albanese C FAU - Waugh, David J J AU - Waugh DJ LA - eng GR - R01 CA129003/CA/NCI NIH HHS/United States GR - MR/J007641/1/MRC_/Medical Research Council/United Kingdom GR - [C11512/A11825/CRUK_/Cancer Research UK/United Kingdom GR - C212/A11342/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120828 PL - Switzerland TA - Eur Urol JT - European urology JID - 7512719 RN - 0 (CXCL8 protein, human) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-8) RN - 0 (Receptors, Interleukin-8A) RN - 0 (Receptors, Interleukin-8B) RN - 0 (Transcription Factors) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) RN - EC 3.1.3.67 (Pten protein, mouse) SB - IM CIN - Eur Urol. 2013 Aug;64(2):189-90; discussion 190-2. PMID: 23000087 MH - Animals MH - Apoptosis MH - Autocrine Communication MH - Carcinoma/*enzymology/genetics/*immunology/pathology MH - Cell Hypoxia MH - Cell Line, Tumor MH - Humans MH - Inflammation Mediators/*metabolism MH - Interleukin-8/genetics/*metabolism MH - Male MH - Mice MH - Mice, Knockout MH - PTEN Phosphohydrolase/*deficiency/genetics MH - Prostatic Neoplasms/*enzymology/genetics/*immunology/pathology MH - RNA Interference MH - Receptors, Interleukin-8A/metabolism MH - Receptors, Interleukin-8B/metabolism MH - *Signal Transduction MH - Time Factors MH - Transcription Factors/metabolism MH - Transfection MH - Up-Regulation PMC - PMC4185293 MID - NIHMS631962 OTO - NOTNLM OT - Apoptosis OT - CXCL8 OT - CXCR2 OT - Hypoxia OT - Inflammation OT - PTEN OT - Prostate cancer EDAT- 2012/09/04 06:00 MHDA- 2014/02/08 06:00 PMCR- 2014/10/05 CRDT- 2012/09/04 06:00 PHST- 2012/06/14 00:00 [received] PHST- 2012/08/17 00:00 [accepted] PHST- 2012/09/04 06:00 [entrez] PHST- 2012/09/04 06:00 [pubmed] PHST- 2014/02/08 06:00 [medline] PHST- 2014/10/05 00:00 [pmc-release] AID - S0302-2838(12)00967-0 [pii] AID - 10.1016/j.eururo.2012.08.032 [doi] PST - ppublish SO - Eur Urol. 2013 Aug;64(2):177-88. doi: 10.1016/j.eururo.2012.08.032. Epub 2012 Aug 28.