Abstract 5171: GRP78 as a potential modulator of cell adhesion markers in metastatic prostate cancer and multiple myeloma

Abstract

Abstract Background: Glucose regulated protein 78 (GRP78) is a resident chaperone of the endoplasmic reticulum and a master regulator of the unfolded protein response under physiological and pathological cell stress conditions. GRP78 is overexpressed in many cancers, regulating a variety of signaling pathways associated with tumor initiation, proliferation, adhesion and invasion which contributes to metastatic spread. GRP78 can also regulate cell survival and apoptotic pathways to alter responsiveness to anticancer drugs. Tumors that reside in or metastasize to the bone and bone marrow (BM) space can develop pro-survival signals through their direct adhesive interactions with stromal elements of this niche thereby resisting the cytotoxic effects of drug treatment. In this study, we report a direct correlation between GRP78 and the adhesion molecule N-cadherin (N-cad), known to play a critical role in the adhesive interactions of multiple myeloma and metastatic prostate cancer with the bone microenvironment. Methods: N-cad expression levels (transcription and protein) were evaluated upon siRNA mediated silencing of GRP78 in the MM.1S multiple myeloma and the PC3 metastatic prostate cancer cell lines. Furthermore, we evaluated the effects of GRP78 knockdown (KD) on epithelial-mesenchymal (EMT) transition markers, morphological changes and adhesion of PC3 cells. Results: We demonstrate that GRP78 KD: 1) induced the concomitant downregulation of N-cad in both PC3 and MM.1S cells, 2) resulted in significant decreases of both N-cad and E-cad protein levels in PC3 cells, 3) induced TGF-β1 and Snail-2 expression, potentially accounting for the observed downregulation of E-cad. Our data also suggests that N-cad regulation via GRP78 KD supersedes the effects of TGF-β1; i.e., N-cad was downregulated in spite of the fact that TGF-β1 expression was significantly increased upon GRP78 KD. Conclusion: This work implicates GRP78 as a modulator of cell adhesion markers in MM and PCa. Our results may have clinical implications underscoring GRP78 as a potential therapeutic target to reduce the adhesive nature of metastatic tumors to the bone niche. Citation Format: Christopher Cultrara, David Sabatino, Jenny Zilberberg. GRP78 as a potential modulator of cell adhesion markers in metastatic prostate cancer and multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5171.