title: Celastrol Induces Autophagy by Targeting AR/miR-101 in Prostate Cancer Cells.
abstract: Autophagy is an evolutionarily conserved process responsible for the degradation and recycling of cytoplasmic components through autolysosomes. Targeting AR axis is a standard strategy for prostate cancer treatment; however, the role of AR in autophagic processes is still not fully understood. In the present study, we found that AR played a negative role in AR degrader celastrol-induced autophagy. Knockdown of AR in AR-positive prostate cancer cells resulted in enhanced autophagy. Ectopic expression of AR in AR-negative prostate cancer cells, or gain of function of the AR signaling in AR-positive cells, led to suppression of autophagy. Since miR-101 is an inhibitor of autophagy and its expression was decreased along with AR in the process of celastrol-induced autophagy, we hypothesize that AR inhibits autophagy through transactivation of miR-101. AR binding site was defined in the upstream of miR-101 gene by luciferase reporter and ChIP assays. MiR-101 expression correlated with AR status in prostate cancer cell lines. The inhibition of celastrol-induced autophagy by AR was compromised by blocking miR-101; while transfection of miR-101 led to inhibition of celastrol-induced autophagy in spite of AR depletion. Furthermore, mutagenesis of the AR binding site in miR-101 gene led to decreased suppression of autophagy by AR. Finally, autophagy inhibition by miR-101 mimic was found to enhance the cytotoxic effect of celastrol in prostate cancer cells. Our results demonstrate that AR inhibits autophagy via transactivation of miR-101, thus combination of miR-101 mimics with celastrol may represent a promising therapeutic approach for treating prostate cancer.
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Guo
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Huang
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Yang
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D011944:Receptors, Androgen / Q000096:biosynthesis*; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: C410798:AR protein, human; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D053978:Pentacyclic Triterpenes; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D014315:Triterpenes; C050414:celastrol