| Autor: |
Kuranaga Y; Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Yu B; Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA., Osuka S; Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Zhang H; Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA., Devi NS; Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA., Bae S; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Van Meir EG; Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA. |
| Abstrakt: |
Glioblastoma (GBM) is a devastating brain cancer for which new effective therapies are urgently needed. 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 αβ1 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin α3. Knockdown of α3-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for α3 in mediating the maturation of integrin β1. In its absence, generation of full length β1 was reduced, immature β1 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting α3 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin α3's role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target. |
