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

Ji Yun Yoon,So Rae Song,Seul Gi Lee,Taeg Kyu Kwon,Seon Min Woo,Seung Un Seo

doi:10.3390/ijms23010017

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.

Highlights

Lucanthone is one of the family of thioxanthenones and is originally synthesized for use as anti-schistosomal drugs [1]
In addition to demonstrating that treatment with lucanthone induces lysosomal membrane permeabilization (LMP), this study indicates that the function of lucanthone as an autophagy inhibitor is attributed to the induction of LMP [3]
We examined whether lucanthone enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells

Summary

Introduction

Lucanthone is one of the family of thioxanthenones and is originally synthesized for use as anti-schistosomal drugs [1]. Lucanthone preferentially intercalates at AT-rich sequences in DNA, resulting in the inhibition of the dual-function base excision repair enzyme apurinic endonuclease-1 (APE1) [2]. In addition to demonstrating that treatment with lucanthone induces lysosomal membrane permeabilization (LMP), this study indicates that the function of lucanthone as an autophagy inhibitor is attributed to the induction of LMP [3]. Inhibition of autophagy is a new alternative in terms of enhancing the anticancer ability of anticancer drugs [4]. Many combined treatments are being developed with the aim of enhancing the activity of chemotherapeutic agents. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, targets the death receptors (DRs; DR4 and 5).

Methods

Results

Conclusion