Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization

Seo, Seung Un; Woo, Seon Min; Lee, Hyun‐Shik; Kim, Sang Hyun; Kang, Sun Chul; Lee, Eun Woo; Min, Kyoung‐jin; Kwon, Taeg Kyu

doi:10.1016/j.redox.2019.101422

Cited by 33 publications

(43 citation statements)

References 59 publications

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“…It can further activate downstream products of the eIF4 complex to promote tumor development, regulate the cell cycle, and inhibit autophagy and apoptosis [ 19 ]. Seo et al [ 25 ] demonstrated that inhibition of mTOR enhanced the chemosensitivity of cancer cells. They also revealed that treatment with mTOR inhibitors reduced tumor size and increased apoptosis in a xenograft model.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, CTSK -KD significantly decreased levels of p-mTOR and p-mTOR/mTOR, which inhibited activation of the mTOR signaling pathway. Previous studies have demonstrated that inhibition of Cathepsin K can induce proteasomal degradation of proteins associated with regulatory mechanisms on the target of rapamycin [ 25 ]. This conclusion is inconsistent with our experiment, which suggests that Cathepsin K may play a role in NSCLC through regulation of the mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, mTOR inhibitors have been widely studied and employed clinically in order to suppress tumor growth and sensitize cells to anticancer drugs. Previous studies have demonstrated that inhibition of Cathepsin K can significantly reduced the phosphorylation of mTOR at S2448 in Caki cells [ 25 ]. Therefore, Cathepsin K may mediate activation of the mTOR signaling pathway in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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The Potential Role of Cathepsin K in Non-Small Cell Lung Cancer

et al. 2020

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(1) Background: Cathepsin K has been found overexpressed in several malignant tumors. However, there is little information regarding the involvement of Cathepsin K in non-small cell lung cancer (NSCLC). (2) Methods: Cathepsin K expression was tested in human NSCLC cell lines A549 and human embryo lung fibroblast MRC-5 cells using Western blot and immunofluorescence assay. Cathepsin K was transiently overexpressed or knocked down using transfection with a recombinant plasmid and siRNA, respectively, to test the effects on cell proliferation, migration, invasion, and on the mammalian target of rapamycin (mTOR) signaling pathway. (3) Results: Expression of Cathepsin K was increased significantly in A549 cells and diffused within the cytoplasm compared to the MRC-5 cells used as control. Cathepsin K overexpression promoted the proliferation, migration, and invasion of A549 cells, accompanied by mTOR activation. Cathepsin K knockdown reversed the above malignant behavior and inhibited the mTOR signaling activation, suggesting that Cathepsin K may promote the progression of NSCLC by activating the mTOR signaling pathway. (4) Conclusion: Cathepsin K may potentially represent a viable drug target for NSCLC treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Potential Role of Cathepsin K in Non-Small Cell Lung Cancer

et al. 2020

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“…To analyze DNA fragmentation, we used death detection ELISA plus kit (Boehringer Mannheim, Indianapolis, IN, USA) according to the manufacturer’s recommendations. To measure DEVDase activity, cells were treated with IITZ-01 and/or TRAIL, harvested, and incubated with reaction buffer containing acetyl-Asp-Glu-Val-Asp p-nitroanilide (Ac-DEVD-pNA) substrate, as previously mentioned [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

“…The assay was performed as described in our previous study [ 45 ]. Cells were co-transfected with HA-tagged ubiquitin (HA-Ub), USP9X/wild type and UPS9X/C1566S plasmid, and treated with MG132 for 12 h. Immunoprecipitation was performed using the anti-survivin, and ubiquitination of endogenous survivin was checked using HRP-conjugated anti-Ub under denaturing conditions.…”

Section: Methodsmentioning

confidence: 99%

Upregulation of DR5 and Downregulation of Survivin by IITZ-01, Lysosomotropic Autophagy Inhibitor, Potentiates TRAIL-Mediated Apoptosis in Renal Cancer Cells via Ubiquitin-Proteasome Pathway

Shahriyar

Seo

Min

et al. 2020

Cancers

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively is able to increase apoptosis in cancer cells as agent with minimum toxicity to noncancerous cells. However, all cancer cells are not sensitive to TRAIL-induced apoptosis. In this study, we showed the sub-lethal concentrations of a lysosomotropic autophagy inhibitor, IITZ-01, sensitizes cancer cells (renal, lung, and breast carcinoma) to TRAIL-induced apoptosis through DR5 upregulation and survivin downregulation through ubiquitin-proteasome pathway. Knockdown of DR5 or overexpression of survivin inhibited combined treatment with IITZ-01 and TRAIL-induced apoptosis. IITZ-01 downregulated protein expression of Cbl, ubiquitin E3 ligase, and decreased expression level of Cbl markedly led to increase DR5 protein expression and TRAIL sensitivity. Moreover, IITZ-01 decreased expression level of survivin protein via downregulation of deubiquitinase ubiquitin-specific protease 9X (USP9X) expression. Taken together, these results provide the first evidence that IITZ-01 enhances TRAIL-mediated apoptosis through DR5 stabilization by downregulation of Cbl and USP9X-dependent survivin ubiquitination and degradation in renal carcinoma cells.

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The roles of ubiquitination‐mediated intrinsic apoptotic signalling in cancer therapy

Che

Lin

2022

Clinical and Translational Dis

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Ubiquitination, a highly versatile process of protein homeostasis, participates in the degradation of the vast majority of cellular proteins. In addition to proteolytic function, ubiquitination can also conduce to modulate cellular processes independent of proteolysis, such as signal transduction, protein trafficking, DNA repair and so on. Apoptosis modulates cell quantity via orderly removing damaged cells effectively and plays a fundamental role in the function of multicellular organisms as well homeostasis, while abnormal regulation of apoptosis can lead to various diseases, especially cancer. Since various tumour cells intrinsically elude apoptotic elimination, emerging strategies targeting induction of apoptosis have become great potential and often necessary cancer therapeutic approaches. Numerous researches have shown that ubiquitination can facilitate or inhibit apoptosis by utilising its proteolytic or non‐proteolytic functions aiming at controlling the levels of key proteins. In this review, we focused on intrinsic apoptosis and summarised how diverse types of ubiquitination regulate intrinsic apoptosis through E3 ligases and deubiquitinating enzymes. Given the mechanisms of ubiquitin‐mediated regulation of intrinsic apoptosis and their physiological relevance, we hope that it will supply more therapeutic strategies for cancer.

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Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization

Cited by 33 publications

References 59 publications

The Potential Role of Cathepsin K in Non-Small Cell Lung Cancer

The Potential Role of Cathepsin K in Non-Small Cell Lung Cancer

Upregulation of DR5 and Downregulation of Survivin by IITZ-01, Lysosomotropic Autophagy Inhibitor, Potentiates TRAIL-Mediated Apoptosis in Renal Cancer Cells via Ubiquitin-Proteasome Pathway

The roles of ubiquitination‐mediated intrinsic apoptotic signalling in cancer therapy

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