Inhibition of endoplasmic reticulum chaperone protein glucose-regulated protein 78 potentiates anti-angiogenic therapy in renal cell carcinoma through inactivation of the PERK/eIF2α pathway.

Kyung Seok Han,Ladan Fazli,Sebastian Frees,Martin E Gleave,Susan Ettinger,Ki Chung Park,Pater A Raven,Alan I So,Sung Joon Hong,Na Li

doi:10.18632/oncotarget.5397

Kyung Seok Han, Ladan Fazli + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.5397

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Journal: Oncotarget	Publication Date: Oct 12, 2015
Citations: 20	License type: cc-by

Affiliation: Yonsei University, University of British Columbia

Abstract

Tumor microenvironments are characterized by decreased oxygen and nutrition due to the rapid and progressive nature of tumors and also stresses induced by several anti-tumor therapies. These intense cell stressors trigger a protective cell survival mechanism heralded by the unfolded protein response (UPR). The UPR is induced by an accumulation of unfolded proteins in the endoplasmic reticulum (ER) following cell starvation. Although the ER stress response is implicated in cytoprotection, its precise role during anti-angiogenic therapy remains unclear. One of the major proteins involved in ER stress is glucose-regulated protein 78 (GRP78), which binds to unfolded proteins and dissociates from membrane-bound ER stress sensors. To determine the role of ER stress responses during anti-angiogenic therapy and the potential role of GRP78 in combined therapy in renal cell carcinoma (RCC), we used GRP78 overexpressing or knockdown RCC cells under hypoxic or hypoglycemic conditions in vitro and in animal models treated with sunitinib. Here, we report that GRP78 plays a crucial role in protecting RCC cells from hypoxic and hypoglycemic stress induced by anti-angiogenic therapy. Knockdown of GRP78 using siRNA inhibited cancer cell survival and induced apoptosis in RCC cells in vitro and also resulted in ER stress-induced apoptosis and hypoxic/hypoglycemic stress-induced apoptosis by inactivating the PERK/eIF-2α pathway. Finally, GRP78 knockdown showed potent suppression of tumor growth and enhanced the antitumor effect of sunitinib in RCC xenografts. Our findings suggest that GRP78 may serve as a novel therapeutic target in combination with anti-angiogenic therapy for the management of RCC.

Highlights

Developed targeted therapies have shown promising results in the treatment of advanced malignancies
To further determine whether anti-angiogenic therapy-induced endoplasmic reticulum (ER) stress is caused by hypoxic stress, hypoglycemic stress, or a combination of both, we examined glucose-regulated protein 78 (GRP78) expression in Caki-1 cells following exposure to hypoxic and/or hypoglycemic conditions
To determine whether ER stress chaperone protein GRP78 is upregulated during anti-angiogenic therapy, we treated Caki-1 xenografts with sunitinib, a multi-tyrosine kinase inhibitor and potent anti-angiogenic agent, and used immunohistochemical staining to examine changes in GRP78 expression in xenografts

Summary

Introduction

Developed targeted therapies have shown promising results in the treatment of advanced malignancies. Anti-angiogenic therapies that target vascular endothelial growth factor (VEGF) signaling have demonstrated remarkable clinical benefits in patients with advanced renal cell carcinoma (RCC) [1,2,3]. One of the most efficacious multi-tyrosine kinase inhibitors targeting VEGF, significantly prolongs progression-free survival in patients with advanced RCC and is a first-line therapy for metastatic RCC [1]. Anti-angiogenic therapy is generally not cytotoxic but rather cytostatic; tumors shrink and regress, but many tumor cells survive antiangiogenic treatment and resume growth following an interval of stability. Once the tumor acquires resistance www.impactjournals.com/oncotarget to the anti-angiogenic agent, the tumor rapidly progresses and the prognosis is very poor, even with second- and third-line treatment options

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