Androgen blocks apoptosis of hormone-dependent prostate cancer cells

K. Kimura, Mark Markowski, C. Bowen, E. P. Gelmann

Research output: Contribution to journalArticle

Abstract

Androgen plays a critical role in the promotion and growth of prostate cancer. Androgen ablation has an expanding role in prostate cancer treatment and is now used to improve the efficacy of radiation therapy in addition to its role in treatment of metastatic disease. Here we show that androgen interferes with induction of prostate cancer cell death induced by a variety of stimuli. The effect of androgen on cell death occurs predominantly by interference with caspase activation and the inhibition of caspase cleavage in both the extrinsic and intrinsic cell death pathways. Androgen inhibited apoptosis induced by both tumor necrosis factor α (TNF-α) and by Fas activation with or without concomitant irradiation. An antiapoptotic effect was seen in the presence of R1881, dihydrotestosterone, and also 17β-estradiol within 24 h of death induction. Sustained inhibition of apoptosis at 72 h was seen only with R1881, dihydrotestosterone, cyproterone acetate, and hydroxyflutamide. Androgen treatment inhibited activation of caspases-8, -7, and -9 by TNF-α +/- irradiation. Androgen attenuated BAX expression and blocked appearance of the proapoptotic p18 fragment of BAX. Androgen also abrogated BID cleavage induced by TNF-α + irradiation that contributed to a decrease in cytochrome c egress from mitochondria induced by TNF-α +/- irradiation. There was also decreased mitochondrial depolarization in response to TNF-α + irradiation. Production of the proapoptotic lipid metabolite ceramide was not affected by androgen, but androgen acted downstream from ceramide generation because R1881 blocked cell-death induction by bacterial sphingomyelinase. Inhibition of phosphoinositol-3-kinase activity by wortmannin induced apoptosis that was also blocked by androgen, but there was no effect on protein levels or phosphorylation of AKT, indicating that R1881 did not interact with survival signaling of phosphoinositol-3-kinase. Lastly, androgen inhibited activation of nuclear factor-κB during death induction, but the effect of androgen on cell death was not mediated by interference with the nuclear factor-κB pathway. The data suggest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli.

Original languageEnglish (US)
Pages (from-to)5611-5618
Number of pages8
JournalCancer Research
Volume61
Issue number14
StatePublished - Jul 15 2001
Externally publishedYes

Fingerprint

Androgens
Prostatic Neoplasms
Hormones
Apoptosis
Metribolone
Cell Death
Tumor Necrosis Factor-alpha
Caspases
Dihydrotestosterone
Ceramides
Phosphotransferases
Cyproterone Acetate
Caspase 7
Sphingomyelin Phosphodiesterase
Caspase 8
Cytochromes c
Estradiol
Mitochondria
Radiotherapy
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kimura, K., Markowski, M., Bowen, C., & Gelmann, E. P. (2001). Androgen blocks apoptosis of hormone-dependent prostate cancer cells. Cancer Research, 61(14), 5611-5618.

Androgen blocks apoptosis of hormone-dependent prostate cancer cells. / Kimura, K.; Markowski, Mark; Bowen, C.; Gelmann, E. P.

In: Cancer Research, Vol. 61, No. 14, 15.07.2001, p. 5611-5618.

Research output: Contribution to journalArticle

Kimura, K, Markowski, M, Bowen, C & Gelmann, EP 2001, 'Androgen blocks apoptosis of hormone-dependent prostate cancer cells', Cancer Research, vol. 61, no. 14, pp. 5611-5618.
Kimura K, Markowski M, Bowen C, Gelmann EP. Androgen blocks apoptosis of hormone-dependent prostate cancer cells. Cancer Research. 2001 Jul 15;61(14):5611-5618.
Kimura, K. ; Markowski, Mark ; Bowen, C. ; Gelmann, E. P. / Androgen blocks apoptosis of hormone-dependent prostate cancer cells. In: Cancer Research. 2001 ; Vol. 61, No. 14. pp. 5611-5618.
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