ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway
Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the...
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/5/2768 |
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| author | Chang-Hoon Lim Xue-Quan Fang Hyeji Kang Taerim Oh Seonghoon Lee Young-Seon Kim Ji-Hong Lim |
| author_facet | Chang-Hoon Lim Xue-Quan Fang Hyeji Kang Taerim Oh Seonghoon Lee Young-Seon Kim Ji-Hong Lim |
| author_sort | Chang-Hoon Lim |
| collection | DOAJ |
| description | Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress–PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i. |
| first_indexed | 2024-04-25T00:29:22Z |
| format | Article |
| id | doaj.art-cb55db815fca453cbf788cbcceb25d76 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-25T00:29:22Z |
| publishDate | 2024-02-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cb55db815fca453cbf788cbcceb25d762024-03-12T16:46:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01255276810.3390/ijms25052768ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK PathwayChang-Hoon Lim0Xue-Quan Fang1Hyeji Kang2Taerim Oh3Seonghoon Lee4Young-Seon Kim5Ji-Hong Lim6Department of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of KoreaDepartment of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of KoreaDepartment of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of KoreaDepartment of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of KoreaDepartment of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of KoreaDepartment of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of KoreaDepartment of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of KoreaUbiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress–PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i.https://www.mdpi.com/1422-0067/25/5/2768chemoresistanceubiquitin-specific protease 7 inhibitorheat shock transcription factor 1endoplasmic reticulum stress |
| spellingShingle | Chang-Hoon Lim Xue-Quan Fang Hyeji Kang Taerim Oh Seonghoon Lee Young-Seon Kim Ji-Hong Lim ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway International Journal of Molecular Sciences chemoresistance ubiquitin-specific protease 7 inhibitor heat shock transcription factor 1 endoplasmic reticulum stress |
| title | ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway |
| title_full | ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway |
| title_fullStr | ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway |
| title_full_unstemmed | ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway |
| title_short | ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway |
| title_sort | er stress activated hsf1 governs cancer cell resistance to usp7 inhibitor based chemotherapy through the perk pathway |
| topic | chemoresistance ubiquitin-specific protease 7 inhibitor heat shock transcription factor 1 endoplasmic reticulum stress |
| url | https://www.mdpi.com/1422-0067/25/5/2768 |
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