Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer

Nooshin Mirkheshti, Sulgi Park, Shoulei Jiang, Jodie Cropper, Sherry L. Werner, Chung-seog Song, Bandana Chatterjee

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathwayselective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors. AR expression, its transcriptional activity, and androgen biosynthesis regulating enzymes CYP17A1, HSD3β1 were reduced by sub-micro molar salinomycin. Estrogen receptor-α expression was unchanged. Loss of phosphorylated AR at serine-81, which is an index for nuclear AR activity, preceded total AR reduction. Rapamycin enhanced the AR protein level without altering phosphoAR-Ser81 and CYP17A1. Inactivation of mTORC1, evident from reduced phosphorylation of mTOR and downstream effectors, as well as AMPK activation led to robust autophagy induction. Apoptosis increased modestly, albeit significantly, by sub-micro molar salinomycin. Enhanced stimulatory TSC2 phosphorylation at Ser-1387 by AMPK, and reduced inhibitory TSC2 phosphorylation at Ser-939/Thr-1462 catalyzed by AKT augmented TSC2/TSC1 activity, which led to mTORC1 inhibition. AMPK-mediated raptor phosphorylation further reduced mTOR's kinase function and mTORC1 activity. Our novel finding on dual inhibition of AR and mTORC1 suggests that salinomycin is potentially active as monotherapy against advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)62240-62254
Number of pages15
JournalOncotarget
Volume7
Issue number38
DOIs
StatePublished - 2016

Fingerprint

Androgen Receptors
Prostatic Neoplasms
AMP-Activated Protein Kinases
Phosphorylation
Castration
Raptors
Neoplastic Stem Cells
mechanistic target of rapamycin complex 1
salinomycin
Autophagy
Sirolimus
Cytoplasmic and Nuclear Receptors
Phosphatidylinositol 3-Kinases
Heterografts
Estrogen Receptors
Serine
Androgens
Phosphotransferases
Apoptosis
Anti-Bacterial Agents

Keywords

  • AMPK
  • Androgen receptor
  • CYP17A1
  • HSD3β1
  • MTORC1

ASJC Scopus subject areas

  • Oncology

Cite this

Mirkheshti, N., Park, S., Jiang, S., Cropper, J., Werner, S. L., Song, C., & Chatterjee, B. (2016). Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer. Oncotarget, 7(38), 62240-62254. https://doi.org/10.18632/oncotarget.11404

Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer. / Mirkheshti, Nooshin; Park, Sulgi; Jiang, Shoulei; Cropper, Jodie; Werner, Sherry L.; Song, Chung-seog; Chatterjee, Bandana.

In: Oncotarget, Vol. 7, No. 38, 2016, p. 62240-62254.

Research output: Contribution to journalArticle

Mirkheshti, N, Park, S, Jiang, S, Cropper, J, Werner, SL, Song, C & Chatterjee, B 2016, 'Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer', Oncotarget, vol. 7, no. 38, pp. 62240-62254. https://doi.org/10.18632/oncotarget.11404
Mirkheshti N, Park S, Jiang S, Cropper J, Werner SL, Song C et al. Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer. Oncotarget. 2016;7(38):62240-62254. https://doi.org/10.18632/oncotarget.11404
Mirkheshti, Nooshin ; Park, Sulgi ; Jiang, Shoulei ; Cropper, Jodie ; Werner, Sherry L. ; Song, Chung-seog ; Chatterjee, Bandana. / Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer. In: Oncotarget. 2016 ; Vol. 7, No. 38. pp. 62240-62254.
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