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Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy
Author(s) -
Shiota Masaki,
Ushijima Miho,
Imada Kenjiro,
Kashiwagi Eiji,
Takeuchi Ario,
Inokuchi Junichi,
Tatsugami Katsunori,
Kajioka Shunichi,
Eto Masatoshi
Publication year - 2019
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23828
Subject(s) - enzalutamide , prostate cancer , medicine , androgen receptor , docetaxel , cancer , oncology , cancer research , prostate , protein kinase b , signal transduction , biology , biochemistry
Background Cigarette smoking is associated with worse outcomes in prostate cancer, whose growth is dependent on androgen receptor (AR) signaling. We aimed to elucidate the biological effect of cigarette smoking on AR signaling and its clinical influence on oncological outcome. Methods Gene expression levels after exposure to tobacco smoke condensate (TSC) were evaluated by quantitative real‐time polymerase chain reaction and Western blot analysis in prostate cancer cells. Cellular sensitivities to enzalutamide and docetaxel after TSC exposure were evaluated using a prostate cancer cell proliferation assay. Prognosis was compared between current smokers and nonsmokers when treated with AR‐axis‐targeting (ARAT) agent enzalutamide and docetaxel. Results Expression of AR variants as well as prostate‐specific antigen was augmented after TSC exposure, which occurred after Akt phosphorylation. These inductions were suppressed by Akt inhibitor LY294002 as well as antioxidant N‐acetylcysteine. Consistently, TSC exposure augmented cellular resistance to enzalutamide. In clinical data, cigarette smoking was associated with worse progression‐free survival and cancer‐specific survival when patients with prostate cancer were treated with ARAT agents but not docetaxel. Conclusions It was suggested that cigarette smoking leads to detrimental oncological outcome when prostate cancer patients are treated with ARAT agents through induction of aberrant AR signaling. Accordingly, we recommend that patients with advanced prostate cancer should refrain from cigarette smoking.