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 pathway-selective 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.
Keywords:
AMPK; CYP17A1; HSD3β1; androgen receptor; mTORC1.
MeSH terms
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AMP-Activated Protein Kinases / metabolism
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Androgen Receptor Antagonists / pharmacology*
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Androgen Receptor Antagonists / therapeutic use
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Animals
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Antibiotics, Antineoplastic / pharmacology*
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Antibiotics, Antineoplastic / therapeutic use
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Apoptosis
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Cell Line, Tumor
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Cell Proliferation
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Estrogen Receptor alpha / metabolism
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Humans
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Male
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Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
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Mechanistic Target of Rapamycin Complex 1 / metabolism
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Mice
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Mice, Nude
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Multienzyme Complexes / metabolism
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PTEN Phosphohydrolase / genetics
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Phosphatidylinositol 3-Kinases
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Phosphorylation
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Progesterone Reductase / metabolism
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms, Castration-Resistant / drug therapy
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Prostatic Neoplasms, Castration-Resistant / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrans / pharmacology*
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Pyrans / therapeutic use
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Receptors, Androgen / metabolism*
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Serine / metabolism
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Signal Transduction
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Sirolimus / pharmacology
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Steroid 17-alpha-Hydroxylase / metabolism
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Steroid Isomerases / metabolism
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism
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Xenograft Model Antitumor Assays
Substances
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3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase
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AR protein, human
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Androgen Receptor Antagonists
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Antibiotics, Antineoplastic
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ESR1 protein, human
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Estrogen Receptor alpha
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Multienzyme Complexes
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Pyrans
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Receptors, Androgen
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TSC1 protein, human
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TSC2 protein, human
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Tsc1 protein, mouse
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Serine
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salinomycin
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Progesterone Reductase
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CYP17A1 protein, human
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Steroid 17-alpha-Hydroxylase
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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AMP-Activated Protein Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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Steroid Isomerases
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Sirolimus