title: miR-30e Blocks Autophagy and Acts Synergistically with Proanthocyanidin for Inhibition of AVEN and BIRC6 to Increase Apoptosis in Glioblastoma Stem Cells and Glioblastoma SNB19 Cells.
abstract: Glioblastoma is the most common and malignant brain tumor in humans. It is a heterogeneous tumor harboring glioblastoma stem cells (GSC) and other glioblastoma cells that survive and sustain tumor growth in a hypoxic environment via induction of autophagy and resistance to apoptosis. So, a therapeutic strategy to inhibit autophagy and promote apoptosis could greatly help control growth of glioblastoma. We created hypoxia using sodium sulfite (SS) for induction of substantiated autophagy in human GSC and glioblastoma SNB19 cells. Induction of autophagy was confirmed by acridine orange (AO) staining and significant increase in Beclin-1 in autophagic cells. microRNA database (miRDB) search suggested that miR-30e could suppress the autophagy marker Beclin-1 and also inhibit the caspase activation inhibitors (AVEN and BIRC6). Pro-apoptotic effect of proanthocyanidin (PAC) has not yet been explored in glioblastoma cells. Combination of 50 nM miR-30e and 150 μM PAC acted synergistically for inhibition of viability in both cells. This combination therapy most effectively altered expression of molecules for inhibition of autophagy and induced extrinsic and intrinsic pathways of apoptosis through suppression of AVEN and BIRC6. Collectively, combination of miR-30e and PAC is a promising therapeutic strategy to inhibit autophagy and increase apoptosis in GSC and SNB19 cells.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
authors.forename: Mrinmay
authors.initials: M
authors.lastname: Chakrabarti
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Ray
mesh_terms: D000165:Acridine Orange / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1 / Q000737:chemistry; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D000860:Hypoxia; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D044945:Proanthocyanidins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013447:Sulfites; D014162:Transfection
chemical_list: C412506:AVEN protein, human; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C401541:BIRC6 protein, human; D000071186:Beclin-1; D051034:Inhibitor of Apoptosis Proteins; C546086:MIRN30b microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D044945:Proanthocyanidins; D013447:Sulfites; C013221:proanthocyanidin; D000165:Acridine Orange; C025026:sodium sulfite