title: PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy.
abstract: PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Chris W D
authors.initials: CW
authors.lastname: Armstrong
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Maxwell
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Chee Wee
authors.initials: CW
authors.lastname: Ong
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Redmond
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Christopher
authors.initials: C
authors.lastname: McCann
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Jessica
authors.initials: J
authors.lastname: Neisen
authors.affiliation: Astex Pharmaceuticals, Cambridge, UK.
authors.forename: George A
authors.initials: GA
authors.lastname: Ward
authors.affiliation: Astex Pharmaceuticals, Cambridge, UK.
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.affiliation: Astex Pharmaceuticals, Cambridge, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Nyree T
authors.initials: NT
authors.lastname: Crawford
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: LaBonte
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Tracy
authors.initials: T
authors.lastname: Robson
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.affiliation: Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: David J J
authors.initials: DJ
authors.lastname: Waugh
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D059248:Chemoradiotherapy; D002633:Chemotaxis / Q000187:drug effects / Q000528:radiation effects; D019175:DNA Methylation / Q000187:drug effects / Q000528:radiation effects; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D008297:Male; D060787:Neoplasm Grading; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D014965:X-Rays
chemical_list: C508606:CXCL8 protein, human; D051034:Inhibitor of Apoptosis Proteins; D016209:Interleukin-8; D011838:Radiation-Sensitizing Agents; D014409:Tumor Necrosis Factor-alpha; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: IAP; PTEN; microenvironment; prostate cancer; radiation