Research Papers:

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

Yang Liu, Konrad Steinestel, Arefeh Rouhi, Milena Armacki, Kristina Diepold, Gabriela Chiosis, Thomas Simmet, Thomas Seufferlein and Ninel Azoitei _

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Oncotarget. 2017; 8:77474-77488. https://doi.org/10.18632/oncotarget.20535

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Yang Liu1,2, Konrad Steinestel3,4, Arefeh Rouhi5, Milena Armacki1, Kristina Diepold1, Gabriela Chiosis6, Thomas Simmet7, Thomas Seufferlein1 and Ninel Azoitei1

1Center for Internal Medicine I, Ulm University, Ulm, Germany

2Department of Gastroenterology and Hepatology, Zhongda Hospital, Southeast University, Nanjing, China

3Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5Center for Internal Medicine III, Ulm University, Ulm, Germany

6Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Institute, New York, NY, USA

7Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany

Correspondence to:

Ninel Azoitei, email: [email protected]

Keywords: tumor angiogenesis, hypoxia, VEGF-A, STK33, HIF-1α

Received: May 13, 2017     Accepted: July 31, 2017     Published: August 24, 2017


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.

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