Lucanthone, Autophagy Inhibitor, Enhances the Apoptotic Effects of TRAIL through miR-216a-5p-Mediated DR5 Upregulation and DUB3-Mediated Mcl-1 Downregulation.

Abstract	A lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated whether lucanthone could enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in various cancer cells. Combined treatment with lucanthone and TRAIL significantly induced apoptosis in human renal carcinoma (Caki and ACHN), prostate carcinoma (PC3), and lung carcinoma (A549) cells. However, combined treatment did not induce apoptosis in normal mouse kidney cells (TCMK-1) and normal human skin fibroblast (HSF). Lucanthone downregulated protein expression of deubiquitinase DUB3, and a decreased expression level of DUB3 markedly led to enhance TRAIL-induced apoptosis. Ectopic expression of DUB3 inhibited combined treatment with lucanthone and TRAIL-induced apoptosis. Moreover, lucanthone increased expression level of DR5 mRNA via downregulation of miR-216a-5p. Transfection of miR-216a-5p mimics suppressed the lucanthone-induced DR5 upregulation. Taken together, these results provide the first evidence that lucanthone enhances TRAIL-induced apoptosis through DR5 upregulation by downregulation of miR-216a-5p and DUB3-dependent Mcl-1 downregulation in human renal carcinoma cells.
Authors	Ji Yun Yoon, Seon Min Woo, Seung Un Seo, So Rae Song, Seul Gi Lee, Taeg Kyu Kwon
Journal	International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 1 (Dec 21 2021) ISSN: 1422-0067 [Electronic] Switzerland
PMID	35008442 (Publication Type: Journal Article)
Chemical References	MCL1 protein, human MIRN216 microRNA, human MicroRNAs Myeloid Cell Leukemia Sequence 1 Protein Receptors, TNF-Related Apoptosis-Inducing Ligand TNF-Related Apoptosis-Inducing Ligand TNFRSF10B protein, human Endopeptidases USP17L2 protein, human Lucanthone
Topics	A549 Cells Animals Autophagy (drug effects) Cell Line, Tumor Cell Proliferation (drug effects) Cell Survival (drug effects) Down-Regulation Drug Synergism Endopeptidases (metabolism) Gene Expression Regulation, Neoplastic (drug effects) Humans Lucanthone (pharmacology) Mice MicroRNAs (genetics) Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism) Neoplasms (drug therapy, genetics, metabolism) PC-3 Cells Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics) TNF-Related Apoptosis-Inducing Ligand (pharmacology) Up-Regulation

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