PMID- 30563499 OWN - NLM STAT- MEDLINE DCOM- 20190327 LR - 20211204 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 18 IP - 1 DP - 2018 Dec 18 TI - GRP78 modulates cell adhesion markers in prostate Cancer and multiple myeloma cell lines. PG - 1263 LID - 10.1186/s12885-018-5178-8 [doi] LID - 1263 AB - 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: GRP78 KD led to concomitant downregulation of N-cad in both tumors types. In PC3 cells, GRP78 KD significantly decreased E-cadherin (E-cad) expression likely associated with the induction in TGF-beta1 expression. Furthermore, GRP78 KD also triggered drastic changes in PC3 cells morphology and decreased their adhesion to osteoblasts (OSB) dependent, in part, to the reduced N-cad expression. 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. FAU - Cultrara, Christopher N AU - Cultrara CN AD - Department of Chemistry and Biochemistry, 400 South Orange Avenue, South Orange, NJ, 07079, USA. FAU - Kozuch, Stephen D AU - Kozuch SD AD - Department of Chemistry and Biochemistry, 400 South Orange Avenue, South Orange, NJ, 07079, USA. FAU - Ramasundaram, Poornema AU - Ramasundaram P AD - Center for Discovery and Innovation, Hackensack University Medical Center, 340 Kingsland Street, Building 102, Nutley, NJ, 07110, USA. FAU - Heller, Claudia J AU - Heller CJ AD - Department of Chemistry and Biochemistry, 400 South Orange Avenue, South Orange, NJ, 07079, USA. FAU - Shah, Sunil AU - Shah S AD - Department of Chemistry and Biochemistry, 400 South Orange Avenue, South Orange, NJ, 07079, USA. FAU - Beck, Adah E AU - Beck AE AD - Department of Chemistry and Biochemistry, 400 South Orange Avenue, South Orange, NJ, 07079, USA. FAU - Sabatino, David AU - Sabatino D AD - Department of Chemistry and Biochemistry, 400 South Orange Avenue, South Orange, NJ, 07079, USA. FAU - Zilberberg, Jenny AU - Zilberberg J AUID- ORCID: 0000-0002-4139-2616 AD - Center for Discovery and Innovation, Hackensack University Medical Center, 340 Kingsland Street, Building 102, Nutley, NJ, 07110, USA. Jenny.Zilberberg@hackensackmeridian.org. LA - eng PT - Journal Article DEP - 20181218 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Cadherins) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (HSPA5 protein, human) RN - 0 (Heat-Shock Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (Transforming Growth Factor beta1) SB - IM MH - Apoptosis/genetics MH - Bone Neoplasms/*genetics/pathology/secondary MH - Cadherins/genetics MH - Cell Adhesion/genetics MH - Cell Line, Tumor MH - Cell Proliferation/genetics MH - Endoplasmic Reticulum Chaperone BiP MH - Epithelial-Mesenchymal Transition/genetics MH - Gene Expression Regulation, Neoplastic MH - Heat-Shock Proteins/antagonists & inhibitors/*genetics MH - Humans MH - Male MH - Multiple Myeloma/*genetics/pathology MH - Neoplasm Metastasis MH - Osteoblasts/pathology MH - PC-3 Cells MH - Prostatic Neoplasms/*genetics/pathology MH - RNA, Small Interfering/genetics MH - Transforming Growth Factor beta1/genetics PMC - PMC6299583 OTO - NOTNLM OT - Cell adhesion OT - Epithelia-mesenchymal transition (EMT) OT - GRP78 OT - Gene knockdown COIS- CONSENT FOR PUBLICATION: Not applicable for either category. COMPETING INTERESTS: The authors declare no competing interests. Jenny Zilberberg and David Sabatino contributed equally to this work. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/12/20 06:00 MHDA- 2019/03/28 06:00 PMCR- 2018/12/18 CRDT- 2018/12/20 06:00 PHST- 2018/07/27 00:00 [received] PHST- 2018/12/04 00:00 [accepted] PHST- 2018/12/20 06:00 [entrez] PHST- 2018/12/20 06:00 [pubmed] PHST- 2019/03/28 06:00 [medline] PHST- 2018/12/18 00:00 [pmc-release] AID - 10.1186/s12885-018-5178-8 [pii] AID - 5178 [pii] AID - 10.1186/s12885-018-5178-8 [doi] PST - epublish SO - BMC Cancer. 2018 Dec 18;18(1):1263. doi: 10.1186/s12885-018-5178-8.