BACKGROUND: Signaling between androgen receptor (AR) and mTOR may be crucial for prostate cancer cells to endure the low androgen and suboptimal nutrient conditions produced by androgen deprivation therapy. MATERIALS AND METHODS: AR and mTOR cross-talk was examined in LNCaP cells exposed to either high or low testosterone. AR and mTOR activities were modified separately using either siRNA knockdown or specific chemical inhibitor. The biological significance of the reciprocal communication was assessed by susceptibility to glucose deprivation-induced cell death. RESULTS: AR positively regulated mTOR activity in both low and high testosterone levels. TSC1 and TSC2, the two negative regulators of mTOR, may be involved since both were up-regulated by AR knockdown. Sub-baseline mTOR increased AR protein levels. However, this effect only occurred with low testosterone. More cells underwent apoptosis if AR function was inhibited during glucose deprivation, which significantly depressed mTOR activity. CONCLUSION: The compensatory increase of AR function due to a repressed mTOR signal is advantageous for survival. Disrupting this loop at the time of initiation of androgen deprivation therapy may delay, or even prevent, the recurrence of prostate cancer.
BACKGROUND: Signaling between androgen receptor (AR) and mTOR may be crucial for prostate cancer cells to endure the low androgen and suboptimal nutrient conditions produced by androgen deprivation therapy. MATERIALS AND METHODS:AR and mTOR cross-talk was examined in LNCaP cells exposed to either high or low testosterone. AR and mTOR activities were modified separately using either siRNA knockdown or specific chemical inhibitor. The biological significance of the reciprocal communication was assessed by susceptibility to glucose deprivation-induced cell death. RESULTS:AR positively regulated mTOR activity in both low and high testosterone levels. TSC1 and TSC2, the two negative regulators of mTOR, may be involved since both were up-regulated by AR knockdown. Sub-baseline mTOR increased AR protein levels. However, this effect only occurred with low testosterone. More cells underwent apoptosis if AR function was inhibited during glucose deprivation, which significantly depressed mTOR activity. CONCLUSION: The compensatory increase of AR function due to a repressed mTOR signal is advantageous for survival. Disrupting this loop at the time of initiation of androgen deprivation therapy may delay, or even prevent, the recurrence of prostate cancer.
Authors: Han C Dan; Mei Sun; Lin Yang; Richard I Feldman; Xue-Mei Sui; Chien Chen Ou; Mark Nellist; Raymond S Yeung; Dicky J J Halley; Santo V Nicosia; Warren J Pledger; Jin Q Cheng Journal: J Biol Chem Date: 2002-07-11 Impact factor: 5.157
Authors: Charlie D Chen; Derek S Welsbie; Chris Tran; Sung Hee Baek; Randy Chen; Robert Vessella; Michael G Rosenfeld; Charles L Sawyers Journal: Nat Med Date: 2003-12-21 Impact factor: 53.440
Authors: Michael A Liss; Lanette Rickborn; John DiGiovanni; Dean Bacich; Linda A DeGraffenried; Manish Parihar; Ian M Thompson; Zelton Dave Sharp Journal: Med Hypotheses Date: 2018-06-05 Impact factor: 1.538
Authors: Akash K Kaushik; Shaiju K Vareed; Sumanta Basu; Vasanta Putluri; Nagireddy Putluri; Katrin Panzitt; Christine A Brennan; Arul M Chinnaiyan; Ismael A Vergara; Nicholas Erho; Nancy L Weigel; Nicholas Mitsiades; Ali Shojaie; Ganesh Palapattu; George Michailidis; Arun Sreekumar Journal: J Proteome Res Date: 2013-12-31 Impact factor: 4.466
Authors: Kelly Kuo; Victoria H J Roberts; Jessica Gaffney; Diana L Takahashi; Terry Morgan; Jamie O Lo; Richard L Stouffer; Antonio E Frias Journal: Endocrinology Date: 2019-08-01 Impact factor: 4.736
Authors: Minoru Kato; Carmen A Banuelos; Yusuke Imamura; Jacky K Leung; Daniel P Caley; Jun Wang; Nasrin R Mawji; Marianne D Sadar Journal: Clin Cancer Res Date: 2015-12-28 Impact factor: 12.531
Authors: I Tsaur; J Makarević; E Juengel; M Gasser; A-M Waaga-Gasser; M Kurosch; M Reiter; S Wedel; G Bartsch; A Haferkamp; C Wiesner; R A Blaheta Journal: Br J Cancer Date: 2012-07-10 Impact factor: 7.640
Authors: Nagireddy Putluri; Ali Shojaie; Vihas T Vasu; Srilatha Nalluri; Shaiju K Vareed; Vasanta Putluri; Anuradha Vivekanandan-Giri; Jeman Byun; Subramaniam Pennathur; Theodore R Sana; Steven M Fischer; Ganesh S Palapattu; Chad J Creighton; George Michailidis; Arun Sreekumar Journal: PLoS One Date: 2011-07-18 Impact factor: 3.240