Lately, the HSP90 client serine/threonine kinase STK33 emerged to be required by cancer cells for their viability and proliferation. However, its mechanistic contribution to carcinogenesis is not clearly understood. Here we report that elevated STK33 expression correlates with advanced stages of human pancreatic and colorectal carcinomas. Impaired proliferation and augmented apoptosis associated with genetic abrogation of STK33 were paralleled by decreased vascularization in tumor xenografts. In line with this, ectopic STK33 not only promoted tumor growth after pharmacologic inhibition of HSP90 using structurally divergent small molecules currently in clinical development, but also restored blood vessel formation in vivo. Mechanistic studies demonstrated that HSP90-stabilized STK33 interacts with and regulates hypoxia-driven accumulation and activation of HIF-1α as well as secretion of VEGF-A in hypoxic cancer cells. In addition, our study reveals a putative cooperation between STK33 and other HSP90 client protein kinases involved in molecular and cellular events through which cancer cells ensure their survival by securing the oxygen and nutrient supply. Altogether, our findings indicate that STK33 interferes with signals from hypoxia and HSP90 to promote tumor angiogenesis and tumor growth.
Pubmed ID: 29100402 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentionsAn American pharmaceutical company aiming to make a difference in the lives of people globally through their medicines, vaccines, biologic therapies and animal health products.
View all literature mentionsCell line HEK293-FT is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A-549 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions