Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model

H. G. Nguyen, J. C. Yang, H. J. Kung, X. B. Shi, D. Tilki, P. N. Lara, R. W. Devere White, A. C. Gao, C. P. Evans

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Macro-autophagy is associated with drug resistance in various cancers and can function as an adaptive response to maintain cell survival under metabolic stresses, including androgen deprivation. Androgen deprivation or treatment with androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or bicalutamide induced autophagy in androgen-dependent and in castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell lines. The autophagic cascade triggered by AR blockage, correlated with the increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed in a subpopulation of C4-2B cells that developed insensitivity to ENZA after sustained exposure in culture. Using flow cytometry and clonogenic assays, we showed that inhibiting autophagy with clomipramine (CMI), chloroquine or metformin increased apoptosis and significantly impaired cell viability. This autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation and the suppression of mammalian target of rapamycin (mTOR) through Raptor phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK significantly inhibited autophagy and promoted cell death in CaP cells acutely or chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is an important survival mechanism in CRPC. Lastly, in vivo studies with mice orthotopically implanted with ENZA-resistant cells demonstrated that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduced tumor growth when compared with control groups (P<0.005). In conclusion, autophagy is as an important mechanism of resistance to ARSI in CRPC. Antiandrogen-induced autophagy is mediated through the activation of AMPK pathway and the suppression of mTOR pathway. Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in vitro and in vivo, implying the therapeutics potential of autophagy inhibitors in the antiandrogen-resistance setting.

Original languageEnglish
Pages (from-to)4521-4530
Number of pages10
JournalOncogene
Volume33
Issue number36
DOIs
Publication statusPublished - Sep 4 2014
Externally publishedYes

Fingerprint

Castration
Autophagy
Heterografts
Prostatic Neoplasms
Androgens
Adenosine Monophosphate
Therapeutics
Protein Kinases
Clomipramine
Androgen Antagonists
Cell Survival
Metformin
Androgen Receptors
Sirolimus
MDV 3100
Raptors
Physiological Stress
Chloroquine
Drug Resistance
Serine

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. / Nguyen, H. G.; Yang, J. C.; Kung, H. J.; Shi, X. B.; Tilki, D.; Lara, P. N.; Devere White, R. W.; Gao, A. C.; Evans, C. P.

In: Oncogene, Vol. 33, No. 36, 04.09.2014, p. 4521-4530.

Research output: Contribution to journalArticle

Nguyen, H. G. ; Yang, J. C. ; Kung, H. J. ; Shi, X. B. ; Tilki, D. ; Lara, P. N. ; Devere White, R. W. ; Gao, A. C. ; Evans, C. P. / Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. In: Oncogene. 2014 ; Vol. 33, No. 36. pp. 4521-4530.
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AU - Shi, X. B.

AU - Tilki, D.

AU - Lara, P. N.

AU - Devere White, R. W.

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AU - Evans, C. P.

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