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GBM, after an initial response to current treatment regimens, develops therapeutic resistance, leading to rapid patient demise. Cancer cells exhibit an inherent elevation of endoplasmic reticulum (ER) stress due to uncontrolled growth and an unfavorable microenvironment, including hypoxia and nutrient deprivation. Cancer cells utilize the unfolded protein response (UPR) to maintain ER homeostasis, and failure of this response promotes cell death. In this study, as integrins are upregulated in cancer, we have evaluated the therapeutic potential of individually targeting all \u03b1\u03b21 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin \u03b13. Knockdown of \u03b13-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for \u03b13 in mediating the maturation of integrin \u03b21. In its absence, generation of full length \u03b21 was reduced, immature \u03b21 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting \u03b13 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin \u03b13\u2019s role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target.<\/jats:p>","DOI":"10.3390\/cells13090753","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T10:56:32Z","timestamp":1714128992000},"page":"753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting Integrin \u03b13 Blocks \u03b21 Maturation, Triggers Endoplasmic Reticulum Stress, and Sensitizes Glioblastoma Cells to TRAIL-Mediated Apoptosis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7418-6520","authenticated-orcid":false,"given":"Yuki","family":"Kuranaga","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"O\u2019Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Yu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Osuka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"O\u2019Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8955-7494","authenticated-orcid":false,"given":"Hanwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narra S.","family":"Devi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9982-3223","authenticated-orcid":false,"given":"Sejong","family":"Bae","sequence":"additional","affiliation":[{"name":"O\u2019Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2444-7707","authenticated-orcid":false,"given":"Erwin G.","family":"Van Meir","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"O\u2019Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1023\/A:1005909127196","article-title":"Bone marrow metastasis in astrocytic gliomata","volume":"37","author":"Hsu","year":"1998","journal-title":"J. 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