STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway

// Yang Liu 1, 2 , Konrad Steinestel 3, 4 , Arefeh Rouhi 5 , Milena Armacki 1 , Kristina Diepold 1 , Gabriela Chiosis 6 , Thomas Simmet 7 , Thomas Seufferlein 1 and Ninel Azoitei 1 1 Center for Internal Medicine I, Ulm University, Ulm, Germany 2 Department of Gastroenterology and Hepatology, Zhongda Hospital, Southeast University, Nanjing, China 3 Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany 4 Gerhard-Domagk-Institute of Pathology, University of Munster, Munster, Germany 5 Center for Internal Medicine III, Ulm University, Ulm, Germany 6 Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Institute, New York, NY, USA 7 Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany Correspondence to: Ninel Azoitei, email: ninel.azoitei@uni-ulm.de Keywords: tumor angiogenesis, hypoxia, VEGF-A, STK33, HIF-1α Received: May 13, 2017      Accepted: July 31, 2017      Published: August 24, 2017 ABSTRACT 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.