HSP90 Supports Tumor Growth and Angiogenesis through PRKD2 Protein Stabilization

被引：57

作者：

Azoitei, Ninel ^{[1
]}

Diepold, Kristina ^{[1
]}

Brunner, Cornelia ^{[2
]}

Rouhi, Arefeh ^{[3
]}

Genze, Felicitas ^{[4
]}

Becher, Alexander ^{[1
]}

Kestler, Hans ^{[5
]}

van Lint, Johan ^{[6
]}

Chiosis, Gabriela ^{[7
]}

Koren, John, III ^{[7
]}

Froehling, Stefan ^{[8
,9
]}

Scholl, Claudia ^{[3
]}

Seufferlein, Thomas ^{[1
]}

机构：

[1] Univ Ulm, Ctr Internal Med 1, D-89081 Ulm, Germany

[2] Univ Ulm, Inst Physiol Chem, D-89081 Ulm, Germany

[3] Univ Ulm, Ctr Internal Med 3, D-89081 Ulm, Germany

[4] Univ Ulm, Dept Urol, D-89081 Ulm, Germany

[5] Univ Ulm, Inst Neuroinformat, D-89081 Ulm, Germany

[6] Katholieke Univ Leuven, Dept Mol Cell Biol, Leuven, Belgium

[7] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY USA

[8] Natl Ctr Tumor Dis, Dept Translat Oncol, Heidelberg, Germany

[9] German Canc Res Ctr, Heidelberg, Germany

来源：

CANCER RESEARCH | 2014年 / 74卷 / 23期

关键词：

HYPOXIA-INDUCIBLE FACTOR-1; NF-KAPPA-B; KINASE-D; SIGNAL-TRANSDUCTION; CANCER-CELLS; CHAPERONE; ACTIVATION; INHIBITORS; CDC37; D2;

D O I：

10.1158/0008-5472.CAN-14-1017

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The kinase PRKD2 (protein kinase D) is a crucial regulator of tumor cell-endothelial cell communication in gastrointestinal tumors and glioblastomas, but its mechanistic contributions to malignant development are not understood. Here, we report that the oncogenic chaperone HSP90 binds to and stabilizes PRKD2 in human cancer cells. Pharmacologic inhibition of HSP90 with structurally divergent small molecules currently in clinical development triggered proteasome-dependent degradation of PRKD2, augmenting apoptosis in human cancer cells of various tissue origins. Conversely, ectopic expression of PRKD2 protected cancer cells from the apoptotic effects of HSP90 abrogation, restoring blood vessel formation in two preclinical models of solid tumors. Mechanistic studies revealed that PRKD2 is essential for hypoxia-induced accumulation of hypoxia-inducible factor-1 alpha (HIF1 alpha) and activation of NF-kappa B in tumor cells. Notably, ectopic expression of PRKD2 was able to partially restore HIF1 alpha and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Taken together, our findings indicate that signals from hypoxia and HSP90 pathways are interconnected and funneled by PRKD2 into the NF-kappa B/VEGF-A signaling axis to promote tumor angiogenesis and tumor growth. (C)2014 AACR.

引用

页码：7125 / 7136

页数：12

共 46 条

[1] Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33 [J].