title: Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitostatin.
abstract: Tumor cell mitochondria are key biosynthetic hubs that provide macromolecules for cancer progression and angiogenesis. Soluble decorin protein core, hereafter referred to as decorin, potently attenuated mitochondrial respiratory complexes and mitochondrial DNA (mtDNA) in MDA-MB-231 breast carcinoma cells. We found a rapid and dynamic interplay between peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the decorin-induced tumor suppressor gene, mitostatin. This interaction stabilized mitostatin mRNA with concurrent accumulation of mitostatin protein. In contrast, siRNA-mediated abrogation of PGC-1α-blocked decorin-evoked stabilization of mitostatin. Mechanistically, PGC-1α bound MITOSTATIN mRNA to achieve rapid stabilization. These processes were orchestrated by the decorin/Met axis, as blocking the Met-tyrosine kinase or knockdown of Met abrogated these responses. Furthermore, depletion of mitostatin blocked decorin- or rapamycin-evoked mitophagy, increased vascular endothelial growth factor A (VEGFA) production, and compromised decorin-evoked VEGFA suppression. Collectively, our findings underscore the complexity of PGC-1α-mediated mitochondrial homeostasis and establish mitostatin as a key regulator of tumor cell mitophagy and angiostasis.
authors.affiliation: From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.forename: Annabel
authors.initials: A
authors.lastname: Torres
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.forename: Rick T
authors.initials: RT
authors.lastname: Owens
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000378:metabolism; D058575:Decorin / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D063306:Mitophagy / Q000187:drug effects* / Q000235:genetics; D008954:Models, Biological; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D058575:Decorin; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; C502303:TCHP protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019859:Proto-Oncogene Proteins c-met
keywords: Angiogenesis; Beclin 1; Extracellular Matrix; Mitochondria; Mitochondrial Membrane Potential; Mitochondrial Respiratory Chain Complexes; Proteoglycan; Receptor-tyrosine Kinase; Small Leucine-rich Proteoglycan