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: Thomas Neill, Annabel Torres, Simone Buraschi, Rick T Owens, Jan B Hoek, Raffaele Baffa, Renato V Iozzo
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 8 Pg. 4952-68 (Feb 21 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24403067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carrier Proteins
• DNA, Mitochondrial
• Decorin
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA, Messenger
• TCHP protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Proto-Oncogene Proteins c-met

Topics

• Breast Neoplasms (metabolism, pathology)
• Carrier Proteins
• Cell Line, Tumor
• DNA, Mitochondrial (metabolism)
• Decorin (pharmacology)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Membrane Potential, Mitochondrial (drug effects, genetics)
• Mitophagy (drug effects, genetics)
• Models, Biological
• Oxidative Phosphorylation (drug effects)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Protein Binding (drug effects, genetics)
• Proto-Oncogene Proteins c-met (metabolism)
• RNA Stability (drug effects, genetics)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Transcription Factors (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Vascular Endothelial Growth Factor A (metabolism)