PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy.
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.
['Armstrong|Chris W D|CW|', 'Maxwell|Pamela J|PJ|', 'Ong|Chee Wee|CW|', 'Redmond|Kelly M|KM|', 'McCann|Christopher|C|', 'Neisen|Jessica|J|', 'Ward|George A|GA|', 'Chessari|Gianni|G|', 'Johnson|Christopher|C|', 'Crawford|Nyree T|NT|', 'LaBonte|Melissa J|MJ|', 'Prise|Kevin M|KM|', 'Robson|Tracy|T|', 'Salto-Tellez|Manuel|M|', 'Longley|Daniel B|DB|', 'Waugh|David J J|DJ|']
D017209:Apoptosis D015153:Blotting, Western D049109:Cell Proliferation D002478:Cells, Cultured D059248:Chemoradiotherapy D002633:Chemotaxis D019175:DNA Methylation D005434:Flow Cytometry D006801:Humans D007124:Immunoenzyme Techniques D051034:Inhibitor of Apoptosis Proteins D016209:Interleukin-8 D008264:Macrophages D008297:Male D060787:Neoplasm Grading D051059:PTEN Phosphohydrolase D011379:Prognosis D011471:Prostatic Neoplasms D011838:Radiation-Sensitizing Agents D014409:Tumor Necrosis Factor-alpha D014965:X-Rays
PTEN prostate cancer IAP radiation microenvironment