Decorin induces tumor cell mitophagy via mitostatin as the molecular basis for the suppression of angiogenesis
The extracellular matrix (ECM) provides a crucially important environment for regulating, integrating, and fine-tuning signaling events pertinent for angiogenesis. Angiogenesis serves as an evolutionarily conserved and fundamental function necessary for sustaining multicellular life. However, pathological angiogenesis represents one of the eight "hallmarks of cancer" permissive for supporting tumorigenesis. The ECM harbors a multitude of instructive cues, either directly embedded within supramolecular structures interpretable to cells or as soluble ligands for receptor engagement. These factors, acting as pro- or anti-angiogenic agents, are subverted for promoting tumorigenesis via neovascularization. Decorin, the archetypical member of the small leucine rich proteoglycan (SLRP) gene family, was originally identified as a key regulator of collagen fibrillogenesis. However, it was soon discovered that decorin functions as a soluble "tumor repressor" via high affinity binding interactions concomitant with protracted degradation of multiple receptor tyrosine kinases (RTKs), including EGFR and Met and inhibiting downstream oncogenes including β-catenin and Myc. Indeed, systemic administration of decorin effectively inhibits tumor growth, angiogenesis, and metastasis where loss of decorin permits malignant progression. Therefore, decorin has earned the title of "the guardian from the matrix." The underlying molecular pathways accountable for decorin-mediated angiostasis remain elusive and poorly understood. Therefore, we discovered mechanisms (via HIF-1α and PGC-1α) responsible for decorin-evoked angiostasis in basal breast carcinoma and identify mitostatin as a novel mitophagic effector. We discovered decorin, in a Met dependent manner, non-canonically represses HIF-1α and multiple downstream targets, such as VEGFA, under normoxia. Simultaneously, decorin transcriptionally induces powerful anti-angiogenic effectors (i.e. TIMP-3 and thrombospondin-1). Differential regulation of these factors collectively function in compromising the pro-angiogenic network. Moreover, we uncovered that decorin triggers rapid secretion of thrombospondin-1 by antagonizing RhoA/ROCK1 via proteosomal degradation of RhoA occurring downstream of EGFR. These data illuminate the multiplicity of decorin antagonizing several RTKs and highlight the importance of signal integration between Met and EGFR for concerted and sustained angiogenic suppression. We found an unexpected role of decorin in dynamically regulating PGC-1α for mitostatin induction. This was achieved via PGC-1α-MITOSTATIN mRNA and mitostatin protein interactions and required for mitostatin induction via decorin. Importantly, we found mitostatin is required for decorin and rapamycin evoked tumor cell mitophagy. Moreover, decorin evoked mitophagy, via mitostatin, was necessary for decorin mediated angiogenic suppression. Collectively, we found novel links between putative ECM components (i.e. decorin, and perhaps related proteoglycans) in attenuating the angiogenic propensity and corresponding energetics of the tumor by subverting HIF-1α and PGC-1α mediated pathways and culminating in mitochondrial turnover and potent angiostasis. Therefore, we have mechanistically dissected the key components required for decorin-mediated angiostasis.
Biology|Molecular biology|Cellular biology
Neill, Thomas, "Decorin induces tumor cell mitophagy via mitostatin as the molecular basis for the suppression of angiogenesis" (2014). ETD Collection for Thomas Jefferson University. AAI3617183.