Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization
Cathepsin K (Cat K) is expressed in cancer cells, but the effect of Cat K on apoptosis is still elusive. Here, we showed that inhibition of Cat K sensitized the human carcinoma cells to anti-cancer drug through up-regulation of Bim. Inhibition of Cat K increased USP27x expression, and knock down of...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-02-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231719314569 |
| _version_ | 1811273675945541632 |
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| author | Seung Un Seo Seon Min Woo Min Wook Kim Hyun-Shik Lee Sang Hyun Kim Sun Chul Kang Eun-Woo Lee Kyoung-jin Min Taeg Kyu Kwon |
| author_facet | Seung Un Seo Seon Min Woo Min Wook Kim Hyun-Shik Lee Sang Hyun Kim Sun Chul Kang Eun-Woo Lee Kyoung-jin Min Taeg Kyu Kwon |
| author_sort | Seung Un Seo |
| collection | DOAJ |
| description | Cathepsin K (Cat K) is expressed in cancer cells, but the effect of Cat K on apoptosis is still elusive. Here, we showed that inhibition of Cat K sensitized the human carcinoma cells to anti-cancer drug through up-regulation of Bim. Inhibition of Cat K increased USP27x expression, and knock down of USP27x markedly blocked Cat K-induced up-regulation of Bim expression. Furthermore, inhibition of Cat K induced proteasome-dependent degradation of regulatory associated protein of mammalian target of rapamycin (Raptor). Down-regulation of Raptor expression increased mitochondrial ROS production, and mitochondria specific superoxide scavengers prevented USP27x-mediated stabilization of Bim by inhibition of Cat K. Moreover, combined treatment with Cat K inhibitor (odanacatib) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reduced tumor growth and induced cell death in a xenograft model. Our results demonstrate that Cat K inhibition enhances anti-cancer drug sensitivity through USP27x-mediated the up-regulation of Bim via the down-regulation of Raptor. Keywords: Apoptosis, Bim, Cathepsin K, USP27x, Mitochondria, Raptor |
| first_indexed | 2024-04-12T23:03:32Z |
| format | Article |
| id | doaj.art-803d5dfcbfb049af9833b60463783c64 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-12T23:03:32Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-803d5dfcbfb049af9833b60463783c642022-12-22T03:12:58ZengElsevierRedox Biology2213-23172020-02-0130Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilizationSeung Un Seo0Seon Min Woo1Min Wook Kim2Hyun-Shik Lee3Sang Hyun Kim4Sun Chul Kang5Eun-Woo Lee6Kyoung-jin Min7Taeg Kyu Kwon8Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 42601, South KoreaDepartment of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 42601, South KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South KoreaKNU-Center for Nonlinear Dynamics, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South KoreaDeaprtment of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41566, South KoreaDepartment of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, South KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South KoreaDepartment of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 42601, South Korea; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Cheombokro, Dong-gu, Daegu, 41061, South Korea; Corresponding author. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Cheombokro, Dong-gu, Daegu, 41061, South Korea. Tel.: +82 790 5301; Fax: +82 790 5219.Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 42601, South Korea; Corresponding author. Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 42601, South Korea. Tel.: +82 53 258 7358; Fax: +82 53 258 7355.Cathepsin K (Cat K) is expressed in cancer cells, but the effect of Cat K on apoptosis is still elusive. Here, we showed that inhibition of Cat K sensitized the human carcinoma cells to anti-cancer drug through up-regulation of Bim. Inhibition of Cat K increased USP27x expression, and knock down of USP27x markedly blocked Cat K-induced up-regulation of Bim expression. Furthermore, inhibition of Cat K induced proteasome-dependent degradation of regulatory associated protein of mammalian target of rapamycin (Raptor). Down-regulation of Raptor expression increased mitochondrial ROS production, and mitochondria specific superoxide scavengers prevented USP27x-mediated stabilization of Bim by inhibition of Cat K. Moreover, combined treatment with Cat K inhibitor (odanacatib) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reduced tumor growth and induced cell death in a xenograft model. Our results demonstrate that Cat K inhibition enhances anti-cancer drug sensitivity through USP27x-mediated the up-regulation of Bim via the down-regulation of Raptor. Keywords: Apoptosis, Bim, Cathepsin K, USP27x, Mitochondria, Raptorhttp://www.sciencedirect.com/science/article/pii/S2213231719314569 |
| spellingShingle | Seung Un Seo Seon Min Woo Min Wook Kim Hyun-Shik Lee Sang Hyun Kim Sun Chul Kang Eun-Woo Lee Kyoung-jin Min Taeg Kyu Kwon Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization Redox Biology |
| title | Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization |
| title_full | Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization |
| title_fullStr | Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization |
| title_full_unstemmed | Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization |
| title_short | Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization |
| title_sort | cathepsin k inhibition induced mitochondrial ros enhances sensitivity of cancer cells to anti cancer drugs through usp27x mediated bim protein stabilization |
| url | http://www.sciencedirect.com/science/article/pii/S2213231719314569 |
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