Z Gastroenterol 2014; 52 - KG188
DOI: 10.1055/s-0034-1386210

Protein kinase D2 modulates tumor growth and tumor angiogenic programme induced by heat shock protein 90

N Azoitei 1, K Diepold 1, S Brobovich 1, C Brunner 2, A Rouhi 3, F Genze 4, A Becher 1, H Kestler 5, J van Lint 6, G Chiosis 7, S Fröhling 8, C Scholl 3, T Seufferlein 1
  • 1Uniklinik Ulm, Innere Medizin I, Ulm, Germany
  • 2Institut für Physiologische Chemie, Ulm, Germany
  • 3Uniklinik Ulm, Innere Medizin III, Ulm, Germany
  • 4Uniklinik Ulm, Klinik für Urologie, Ulm, Germany
  • 5Universität Ulm, Institut für Neuroinformatik, Ulm, Germany
  • 6Katholieke Universiteit, Department of Molecular Cell Biology, Leuven, Belgium
  • 7Sloan-Kettering Institute, Department of Molecular Pharmacology and Chemistry, New York, United States
  • 8National Center for Tumor Diseases and German Cancer Research Center, Department of Translational Oncology, Heidelberg, Germany

Introduction: Heat shock protein 90 (HSP90) serves as an ATP-dependent molecular stabilizer of diverse signaling proteins, including many kinases that are involved in cell proliferation and survival. Protein kinase D2 (PRKD2) is a serine-threonine kinase that belongs to the calcium/calmodulin-dependent protein kinase superfamily. We have recently shown that PRKD2 is a crucial regulator of tumor cell – endothelial cell communication in gastrointestinal tumors.

Aim: The aim of this study was to investigate whether HSP90 might contribute to tumor growth and tumor angiogenesis through PRKD2 protein stabilization.

Results: In this study we have revealed PRKD2 as a novel client for HSP90 chaperone in cancer cells. Depletion of PRKD2 protein following pharmacological inhibition of HSP90 complex dramatically enhanced tumor cell death in vitro in various human cancer cell lines belonging to different tumor entities and in in vivo tumor xenograft in nude mice. Furthermore, pharmacological inhibition of HSP90 was associated with impaired blood vessel formation in vivo. The fact that PRKD2 overexpression restored vascularization and cell viability after HSP90 inhibition, suggests the involvement of PRKD2 in these HSP90 inhibitor-induced effects.

Conclusion: Our data propose PRKD2 degradation through HSP90 inhibition as a putative strategy to hit two important cancer characteristics – angiogenesis and cell viability – with one drug. This study is of potential high value for cancer therapy since several HSP90 (including PU-H71 and STA-9090 used here) and PRKD2 inhibitors are currently in clinical trials or under development respectively.