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.

The miR‐203/SNAI2 axis regulates prostate tumor growth, migration, angiogenesis and stemness potentially by modulating GSK‐3β/β‐CATENIN signal pathway

“…Deregulation of miRNAs contributes to the development of multiple cancers, including PCa. For instance, downregulation of tumor suppressor miRNAs in PCa, including miR-101, miR-126*, miR-145, miR-146a, miR-224, miR-330, miR-34a, and miR-200 family, was found to be associated with advanced clinical stage and tumor metastasis, and ectopic expression of oncogenic miR-NAs, including miR-221/-222, miR-21, miR-141, miR-18a and miR-125b, indicates a higher risk of PCa progression (3)(4)(5)(6)(7)(8)(9)(10).…”

Octreotide Alleviates Autophagy by Up-Regulation of MicroRNA-101 in Intestinal Epithelial Cell Line Caco-2

“…Yu et al have also proven that miR-217 acts as a downstream effector of long non-coding RNA CRNDE in Caco-2 cells [36]. In addition, mounting evidence has revealed the inhibitory effects of miR-101 on autophagy in tumor cells [15,16]. Considering the effects of OCT on autophagy, we hypothesized that miR-101 might be a downstream effector of OCT and further explored the potential interaction between miR-101 and OCT treatments in LPS-treated Caco-2 cells.…”

“…Autophagy in human hepatocellular carcinoma cells was repressed by miR-101 [15]. Abnormal up-regulation of miR-101 might suppress autophagy in prostate cancer cells [16]. TGF-β-activated kinase 1 (TAK1) is a MAP kinase kinase kinase which can be activated by toll-like receptors (TLRs).…”

Long Non-Coding RNA CRNDE Regulates Angiogenesis in Hepatoblastoma by Targeting the MiR-203/VEGFA Axis

“…miRNAs are small non-protein-coding sequences that consist of approximately 20-24 nucleotides and suppress target mRNA translation by post-transcriptionally binding to the 3′ untranslated region (3′UTR). Previous reports have suggested that miRNAs are involved in the regulation of a variety of physiological and pathological processes, including tumour growth, migration, and angiogenesis [14][15][16]. has been demonstrated to be downregulated in a number of malignant diseases, including bladder cancer, cervical cancer, breast cancer, prostate cancer, and hepatocellular carcinoma [17][18][19][20][21].…”