Molecular Chaperone gp96 Is a Novel Therapeutic Target of Multiple Myeloma

Abstract

Purpose gp96 (grp94) is a key downstream chaperone in the ER to mediate unfolded protein response (UPR) and the pathogenesis of multiple myeloma (MM) is closely linked to dysregulated UPR. In this study, we aimed to determine the roles of gp96 in the initiation and progression of MM in vivo and in vitro. Experimental design We generated a mouse model with over-expression of XBP1s and conditional deletion of gp96 in B cell compartment simultaneously to identify the roles of gp96 in the development of MM in vivo. Using a shRNA system, we silenced gp96 in multiple human MM cells and examined the effect of gp96 knockdown on MM cells by cell proliferation, cell cycle analysis, apoptosis assay, immunohistochemistry and human myeloma xenograft model. The anti-cancer activity of gp96 selective inhibitor, WS13 was evaluated by apoptosis assay and MTT assay. Results Genetic deletion of gp96 in XBP1s-Tg mice attenuates multiple myeloma. Silencing of gp96 causes severe compromise in human MM cell growth through inhibiting Wnt-LRP-survivin pathway. We also confirmed that knockdown of gp96 decreased human MM growth in a murine xenograft model. The targeted gp96 inhibitor induced apoptosis and blocked MM cell growth, but did not induce apoptosis in pre-B leukemic cells. We have demonstrated that myeloma growth is dependent on gp96 both genetically and pharmacologically. Conclusions gp96 is essential for MM cell proliferation and survival, suggesting that gp96 is a novel therapeutic target for multiple myeloma.

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

“…The relative importance of the four HSP90 paralogs with respect to cancer treatment remains poorly understood. Although inhibition or downregulation of GRP94 inhibits growth and induces apoptosis in human multiple myeloma and HER2-expressing cell lines (39,40), the role of GRP94 in liver tumorigenesis remains controversial, with recent studies indicating the potential for GRP94 to act as both a tumor suppressor and an oncogene (41,42). Inhibition of TRAP1 by a mitochondria-directed variant of 17-AAG leads to specific apoptosis in cancer cells (43); however, TRAP1 may also play, in a context-dependent manner, a tumor suppressor or an oncogene role (44).…”

Hsp90 as a therapeutic target in endocrinology: current evidence

“…157,158 As already noted, GRP94 deficiency in human multiple myeloma cells resulted in apoptosis through inhibition of the Wnt-survivin pathway. 70 Although the pan-Hsp90 inhibitors showed potential as therapeutic agents for multiple myeloma, the role of individual Hsp90 isoforms and family members in these treatments was not determined. [159][160][161] The GRP94-specific inhibitor, PU-WS13, was shown to induce apoptosis and block the growth of multiple myeloma cells, yet did not induce death in pre-B …”

“…69 Genetic deletion of GRP94 attenuates multiple myeloma in a mouse model of the disease. 70 Additionally, silencing GRP94 compromised human multiple myeloma cell growth. 70 In the absence of GRP94, LRP6 is prevented from reaching the cell surface, thus inhibiting the proproliferative and prosurvival Wnt-β-catenin signaling pathway.…”

“…70 Additionally, silencing GRP94 compromised human multiple myeloma cell growth. 70 In the absence of GRP94, LRP6 is prevented from reaching the cell surface, thus inhibiting the proproliferative and prosurvival Wnt-β-catenin signaling pathway. 57,70 A similar mechanism has been proposed for the attenuation of inflammatory colorectal cancer.…”

“…70 In the absence of GRP94, LRP6 is prevented from reaching the cell surface, thus inhibiting the proproliferative and prosurvival Wnt-β-catenin signaling pathway. 57,70 A similar mechanism has been proposed for the attenuation of inflammatory colorectal cancer. High levels of GRP94 are linked to the control of macrophage-specific Toll-like receptors (TLRs), leading to the production of proinflammatory cytokines and promotion of inflammatory-associated cancer in the colon.…”