Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2

Siting Feng, Qizhu Tang, Meng Sun, Yeon Chun Jae, Christopher P Evans, Allen C Gao

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)665-671
Number of pages7
JournalMolecular Cancer Therapeutics
Volume8
Issue number3
DOIs
StatePublished - Mar 1 2009

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Interleukin-6
Prostatic Neoplasms
Androgens
bicalutamide
Nonsteroidal Anti-Androgens
Therapeutics
Androgen Receptors
Small Interfering RNA
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2. / Feng, Siting; Tang, Qizhu; Sun, Meng; Jae, Yeon Chun; Evans, Christopher P; Gao, Allen C.

In: Molecular Cancer Therapeutics, Vol. 8, No. 3, 01.03.2009, p. 665-671.

Research output: Contribution to journalArticle

Feng, Siting ; Tang, Qizhu ; Sun, Meng ; Jae, Yeon Chun ; Evans, Christopher P ; Gao, Allen C. / Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2. In: Molecular Cancer Therapeutics. 2009 ; Vol. 8, No. 3. pp. 665-671.
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abstract = "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.",
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