TY - JOUR
T1 - DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis
AU - Zhou, J.
AU - Ning, Z.
AU - Wang, B.
AU - Yun, E. J.
AU - Zhang, T.
AU - Pong, R. C.
AU - Fazli, L.
AU - Gleave, M.
AU - Zeng, J.
AU - Fan, J.
AU - Wang, X.
AU - Li, L.
AU - Hsieh, J. T.
AU - He, D.
AU - Wu, K.
N1 - Funding Information:
Acknowledgements. This work was supported by grants from the National Natural Science Foundation of China (NSFC 81202014 to KW and NSFC 81130041 to DH), the Fundamental Research Funds for the Central Universities (to KW), the scholarship from China Scholarship Council (CSC 2009628126 to KW), the Terry Fox Foundation of the National Cancer Institute of Canada, the NIH Pacific Northwest Prostate Specialized Programs of Research Excellence (to MG), the 973 Program of China (grant 2012CB518300 to LL) and the United States Army Grant (W81XWH-11-1-0491 to JTH).
Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (NSFC 81202014 to KW and NSFC 81130041 to DH), the Fundamental Research Funds for the Central Universities (to KW), the scholarship from China Scholarship Council (CSC 2009628126 to KW), the Terry Fox Foundation of the National Cancer Institute of Canada, the NIH Pacific Northwest Prostate Specialized Programs of Research Excellence (to MG), the 973 Program of China (grant 2012CB518300 to LL) and the United States Army Grant (W81XWH-11-1-0491 to JTH).
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP- / - mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death.[[ampi]]copy;2015 Macmillan Publishers Limited All rights reserved 2041-4889/15.
AB - Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP- / - mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death.[[ampi]]copy;2015 Macmillan Publishers Limited All rights reserved 2041-4889/15.
UR - http://www.scopus.com/inward/record.url?scp=84975297278&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84975297278&partnerID=8YFLogxK
U2 - 10.1038/cddis.2015.289
DO - 10.1038/cddis.2015.289
M3 - Article
C2 - 26512963
AN - SCOPUS:84975297278
SN - 2041-4889
VL - 6
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 10
M1 - e1955
ER -