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

Thomas Neill,Annabel Torres,Simone Buraschi,Rick T Owens,Jan B Hoek,Raffaele Baffa,Renato V Iozzo

doi:10.1074/jbc.m113.512566

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.

Highlights

Decorin functions as a soluble tumor repressor via binding receptor-tyrosine kinases, such as Met, to curb rampant tumor neovascularization
We discovered that decorin evoked mitostatin production via the Met receptor, thereby triggering a signaling cascade leading to a mitostatin-dependent mitophagy associated with a negative feedback control on vascular endothelial growth factor A (VEGFA) transcription, indirectly attenuating tumor angiogenesis
Decorin Requires Met for Suppression of Oxidative Phosphorylation—Decorin transcriptionally suppresses several critical oncogenes under normoxia including Myc and HIF-1␣ [42], which play instrumental roles in the reprogramming of metabolism, as it pertains to the dichotomy of aerobic glycolysis and mitochondrial respiration (4, 59 – 61)

Summary

Background

Decorin functions as a soluble tumor repressor via binding receptor-tyrosine kinases, such as Met, to curb rampant tumor neovascularization. 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. The molecular underpinnings remain unclear, loss of tumor suppressor genes, alternate mRNA splicing of metabolic enzymes, conventional oncogenes, and receptor-tyrosine kinase signaling have all been shown to actively participate in mitochondrial reprogramming [2, 3]. Decorin promotes an anti-angiogenic tumor microenvironment by acting as a partial EGF receptor agonist for rapid secretion of thrombospondin-1 [43], a central player in angiogenesis [44], fibrosis [45], and cardiovascular function [46] These studies have firmly established decorin as an endogenous tumoricidal agent [47] and is further supported by genetic evidence where loss of the decorin gene is permissive for tumorigenesis [48, 49]. We further discovered a novel interaction between PGC-1␣ and mitostatin, and this interaction led to stabilization of mitostatin mRNA and concurrent accumulation of mitostatin protein

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION