Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2.
The standard treatment for advanced, androgen-responsive prostate cancer is androgen deprivation therapy with or without a nonsteroidal antiandrogen, such as bicalutamide. Although maximal androgen blockade exhibits favorable responses in the majority of patients, prostate cancer eventually progresses to an androgen-refractory stage. The mechanism underlying bicalutamide resistance in the course of prostate cancer progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of CRPC. Herein, we explored an association between IL-6 and bicalutamide resistance. To study this, series of lower and higher passages of LNCaP cell sublines generated by long-term exposure to IL-6 were used. The cells from higher passages of LNCaP treated with IL-6 developed resistance to bicalutamide treatment compared with parental LNCaP cells. The levels of transcriptional intermediary factor 2 (TIF2) in IL-6-treated LNCaP cells were found to be significantly higher than parental LNCaP cells. Down-regulation of TIF2 expression via short hairpin RNA in IL-6-treated LNCaP cells sensitized these cells to bicalutamide treatment, whereas overexpression of TIF2 in the parental LNCaP cells increased resistance to bicalutamide. Furthermore, overexpression of IL-6 attenuated bicalutamide-mediated blockage of androgen-induced androgen receptor nuclear translocation and recruitment. These results show that overexpression of IL-6 increases the resistance of prostate cancer cells to bicalutamide via TIF2. Overexpression of IL-6 not only plays an important role in prostate cancer progression but also contributes to bicalutamide resistance. Our studies suggest that bicalutamide-IL-6-targeted adjunctive therapy may lead to a more effective intervention than bicalutamide alone.
Feng
Siting
S
Department of Urology and Cancer Center, University of California at Davis Medical Center Research III, Suite 1300, 4645 2nd Avenue, Sacramento, CA 95817, USA.
Tang
Qizhu
Q
Sun
Meng
M
Chun
Jae Yeon
JY
Evans
Christopher P
CP
Gao
Allen C
AC
D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D014105:Tosyl Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D015850:Interleukin-6; C498001:NCOA2 protein, human; D009570:Nitriles; D051958:Nuclear Receptor Coactivator 2; D014105:Tosyl Compounds; C053541:bicalutamide