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Cited by 212Autophagy in Disease and TherapyProstate Cancer Treatment and ResearchPI3K/AKT/mTOR signaling in cancer

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

Open access
Nguyen, H G, Yang, J C, Kung, H-J, Shi, X-B, Tilki, D, Lara, P N, DeVere White, R W, Gao, A C +1 more·2014·Oncogene
DOI 10.1038/onc.2014.25PMC PMC4155805
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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.

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  • AMPK activation by metformin leads to inhibition of mTOR via TSC2, resulting in reduced cell growth and proliferation.

    “AMPK activation by metformin leads to inhibition of mammalian target of rapamycin (mTOR) via tuberous sclerosis complex 2 (TSC2), resulting in reduced cell growth and proliferation [19].”

    From Enzalutamide Plus Metformin Versus Enzalutamide Alone in Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 2 Trial (SAKK 08/14). (2026) · cites this paper as [19]

    The Discussion says metformin modulates autophagy through AMPK and mTOR signaling, and separately describes AMPK inhibition of mTORC1 through TSC2 (page not provided). The Results report only a marginal reduction in tumor size with metformin alone. The paper does not establish that metformin acts through TSC2 to reduce cell growth or proliferation; its own mechanistic experiments concern enzalutamide and Raptor. (LLM, conf=0.86)

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Research works printed but not linked: 33

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Authors
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.
Affiliations
  • University of California Davis Medical Center (US)
  • UC Davis Comprehensive Cancer Center (US)
Corresponding author
Evans, C P
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2014-03-24
Volume
33
Issue
36
Pages
4521-4530
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2014.25
PMC
PMC4155805
OpenAlex
W2009607678
Cited by
212
References
39
Citations by year
2026: 10 · 2025: 14 · 2024: 22 · 2023: 18 · 2022: 20 · 2021: 12 · 2020: 18 · 2019: 12 · 2018: 24 · 2017: 14 · 2016: 21 · 2015: 18 · 2014: 9
FWCI
15.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Defense
  • American Association for Cancer Research
  • Prostate Cancer Foundation
  • Entertainment Industry Foundation
  • Movember Foundation
  • Astellas Pharma
  • National Institutes of Health
  • Stand Up To Cancer (DT0812)
  • National Cancer Institute (R01CA165263, P30CA093373)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
autophagy, enzalutamide resistance, castration-resistant prostate cancer, androgen receptor pathway inhibitors, androgen deprivation therapy, AMPK, mTOR, Raptor phosphorylation, clomipramine, metformin, chloroquine, apoptosis, autophagy inhibitors, xenograft tumor growth
MeSH terms
Animals, Autophagy, Benzamides, Chloroquine, Clomipramine, Humans, Male, Metformin, Nitriles, Phenylthiohydantoin, Signal Transduction, Gene Expression Regulation, Neoplastic, Mice, SCID, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Androgen Receptor Antagonists, Prostatic Neoplasms, Castration-Resistant

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