Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30

Ding Yan,Qingtian Huang,Q Ping Dou,Wenshuang Sun,Xin Chen,Shuhui Lin,Leyi Yao,Qianqian Yang,Peiquan Zhang,Jinbao Liu,Xiaofen Li

doi:10.1038/s41420-021-00599-6

Abstract

Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

Highlights

Global epidemiological data identified lung cancer as the second frequently diagnosed cancer and the most frequent cause of death from cancer in men [1]
In Given the significant role of mitochondria in apoptotic pathway addition, our previous studies have shown that treatment with [29], we investigated whether treatment with aumdubin induced auranofin induced proteasomal DUB inhibition in a series of mitochondrial apoptosis in lung cancer cells
We first tested whether aumdubin could induce reactive oxygen species (ROS) by targeting thioredoxin reductases (TrxR) in lung measured the dynamic changes of cytochrome c levels in cytoplasm and mitochondria by western blotting of isolated fractions, and found that aumdubin treatment increased the levels of cytochrome c in cytosol while deceased its levels in mitochondria (Fig. 3D, E)

Summary

INTRODUCTION

Global epidemiological data identified lung cancer as the second frequently diagnosed cancer and the most frequent cause of death from cancer in men [1]. Posttranslational modifications (e.g., phosphorylation and ubiquitination) play crucial roles in the regulation of the function and stabilization of Bax proteins. USP30, a DUB present in the mitochondrial outer membrane, plays an important role in the regulation of mitochondrial morphology and mitophagy [15, 16]. We obvious difference in the body weight of the nude mice and provide evidence that aumdubin, a new auranofin derivative, changes in hematoxylin-eosin staining of organs (such as heart, inhibits the mitochondrial outer membrane DUB USP30 and liver, spleen, lung, and kidney) among these three groups (Fig. 2E, induces Bax-dependent mitochondrial apoptosis in F), indicating that aumdubin at the used dose has no toxicity. DUB inhibition and apoptosis induction in xenograft tissues were observed by immunohistochemistry staining of ubiquitinated proteins and cleaved caspase 3 in the aumdubin

RESULTS

Yan et al 3

DISCUSSION