Decorin induces rapid secretion of thrombospondin-1 in basal breast carcinoma cells via inhibition of Ras homolog gene family, member A/Rho-associated coiled-coil containing protein kinase 1.
Pathological neovascularization relies on an imbalance between potent proangiogenic agents and equally effective antiangiogenic cues. Collectively, these factors contribute to an angiogenic niche within the tumor microenvironment. Oncogenic events and hypoxia contribute to augmented levels of angiokines, and thereby activate the so-called angiogenic switch to promote aggressive tumorigenic and metastatic growth. Soluble decorin functions as a paracrine pan-inhibitor of receptor tyrosine kinases, such as Met and epidermal growth factor receptor, and thus is capable of suppressing angiogenesis under normoxia. This leads to noncanonical repression of hypoxia-inducible factor 1-alpha and vascular endothelial growth factor A (VEGFA), and concurrent induction of thrombospondin-1. The substantial induction of endogenous tumor cell-derived thrombospondin-1, a potent antiangiogenic effector, led us to the discovery of an unexpected secretory phenotype occurring very rapidly (within 5 min) after decorin treatment of the triple-negative basal breast carcinoma cell line MDA-MB-231. Surprisingly, the effect was not mediated by Met receptor antagonism, as initially hypothesized, but required epidermal growth factor receptor signaling to achieve swift and robust thrombospondin-1 release. Furthermore, this effect was ultimately dependent on the prompt degradation of Ras homolog gene family member A, via the 26S proteasome, leading to direct inactivation of Rho-associated coiled-coil containing protein kinase 1. The latter led to derepression of thrombospondin-1 secretion. Collectively, these data provide a novel mechanistic role for Rho-associated coiled-coil containing protein kinase 1, in addition to providing the first conclusive evidence of decorin exclusively targeting a receptor tyrosine kinase to achieve a specific effect. The overall effects of soluble decorin on the tumor microenvironment would cause an immediately-early as well as a sustained antiangiogenic response in vivo.
Department of Pathology, Anatomy, and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Thomas
T
Neill
Holly R
HR
Jones
Zoe
Z
Crane-Smith
Rick T
RT
Owens
Liliana
L
Schaefer
Renato V
RV
Iozzo
D000577:Amides / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002280:Basal Cell Carcinoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D058575:Decorin / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009389:Neovascularization, Pathologic / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D055571:Secretory Pathway; D015398:Signal Transduction; D013997:Time Factors; D059016:Tumor Microenvironment; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000577:Amides; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D058575:Decorin; D011725:Pyridines; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C481348:SPZ1 protein, human; C066737:RHOA protein, human; C108830:Y 27632; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D020742:rhoA GTP-Binding Protein