Decorin Induces Mitophagy in Breast Carcinoma Cells via Peroxisome Proliferator- activated Receptor gamma Coactivator-1 alpha ( PGC-1 alpha) and Mitostatin*

作者：Neill Thomas; Torres Annabel; Buraschi Simone; Owens Rick T; Hoek Jan B; Baffa Raffaele; Iozzo Renato V^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(8): 4952-4968.

DOI：10.1074/jbc.M113.512566

• Angiogenesis
• Extracellular Matrix
• Mitochondria
• Proteoglycan
• Receptor-tyrosine Kinase
• Beclin 1
• Mitochondrial Membrane Potential
• Mitochondrial Respiratory Chain Complexes
• Small Leucine-rich Proteoglycan

Background: Decorin functions as a soluble tumor repressor via binding receptor-tyrosine kinases, such as Met, to curb rampant tumor neovascularization. Results: Decorin evokes tumor cell mitophagy through dynamic co-regulation of PGC-1 and mitostatin via physical interactions between PGC-1 and mitostatin Conclusion: Decorin requires mitostatin to evoke mitophagy as the underlying basis for angiogenic attenuation. Significance: We have identified mitostatin as a novel mitophagic effector.
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 coactivator-1 (PGC-1) 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-1-blocked decorin-evoked stabilization of mitostatin. Mechanistically, PGC-1 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-1-mediated mitochondrial homeostasis and establish mitostatin as a key regulator of tumor cell mitophagy and angiostasis.

• 出版日期2014-2-21