Courtney Clark, Amir Barzegar Behrooz, Simone C Da Silva Rosa, Jaodi Jacobs, Xiaohui Weng, Abhay Srivastava, Rui Vitorino, Sudharsan Rao Ande, Amir Ravandi, Sanjiv Dhingra, Stevan Pecic, Donald Miller, Shahla Shojaei, Saeid Ghavami
{"title":"BCL2L13 Influences Autophagy and Ceramide Metabolism without Affecting Temozolomide Resistance in Glioblastoma","authors":"Courtney Clark, Amir Barzegar Behrooz, Simone C Da Silva Rosa, Jaodi Jacobs, Xiaohui Weng, Abhay Srivastava, Rui Vitorino, Sudharsan Rao Ande, Amir Ravandi, Sanjiv Dhingra, Stevan Pecic, Donald Miller, Shahla Shojaei, Saeid Ghavami","doi":"10.1101/2024.08.23.609447","DOIUrl":null,"url":null,"abstract":"Temozolomide (TMZ) resistance in glioblastoma (GB) poses a significant therapeutic challenge. We developed a TMZ-resistant (TMZ-R) U251 GB model, revealing distinct differences in cell viability, apoptosis, autophagy, and lipid metabolism between TMZ-R and non-resistant (TMZ-NR) cells. TMZ-NR cells exhibited heightened sensitivity to TMZ-induced apoptosis, while TMZ-R cells-maintained viability. Autophagy flux was completely inhibited in TMZ-R cells, indicated by LC3βII and SQSTM1 accumulation. BCL2L13, which showed higher expression in TMZ-R cells, demonstrated increased interaction with Ceramide Synthase 6 (CerS6) and reduced interaction with Ceramide Synthase 2 (CerS2) in TMZ-NR cells. BCL2L13 knockdown (KD) disrupted autophagy flux, decreasing autophagosome accumulation in TMZ-R cells while increasing it in TMZ-NR cells. These changes contributed to altered ceramide profiles, where TMZ-R cells displayed elevated levels of Cer 16:0, 18:0, 20:0, 22:0, 24:0, and 24:1. Our findings highlight BCL2L13 and altered ceramide metabolism as potential therapeutic targets to overcome TMZ resistance in GB.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"20 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Cancer Biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.08.23.609447","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Temozolomide (TMZ) resistance in glioblastoma (GB) poses a significant therapeutic challenge. We developed a TMZ-resistant (TMZ-R) U251 GB model, revealing distinct differences in cell viability, apoptosis, autophagy, and lipid metabolism between TMZ-R and non-resistant (TMZ-NR) cells. TMZ-NR cells exhibited heightened sensitivity to TMZ-induced apoptosis, while TMZ-R cells-maintained viability. Autophagy flux was completely inhibited in TMZ-R cells, indicated by LC3βII and SQSTM1 accumulation. BCL2L13, which showed higher expression in TMZ-R cells, demonstrated increased interaction with Ceramide Synthase 6 (CerS6) and reduced interaction with Ceramide Synthase 2 (CerS2) in TMZ-NR cells. BCL2L13 knockdown (KD) disrupted autophagy flux, decreasing autophagosome accumulation in TMZ-R cells while increasing it in TMZ-NR cells. These changes contributed to altered ceramide profiles, where TMZ-R cells displayed elevated levels of Cer 16:0, 18:0, 20:0, 22:0, 24:0, and 24:1. Our findings highlight BCL2L13 and altered ceramide metabolism as potential therapeutic targets to overcome TMZ resistance in GB.