Suppression of stress induction of the 78-kilodalton glucose regulated protein (GRP78) in cancer by IT-139, an anti-tumor ruthenium small molecule inhibitor.

Autor:	Bakewell SJ; Intezyne Technologies, Inc., Tampa 33612, FL, USA., Rangel DF; Department of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles 90089, CA, USA., Ha DP; Department of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles 90089, CA, USA., Sethuraman J; Intezyne Technologies, Inc., Tampa 33612, FL, USA., Crouse R; Intezyne Technologies, Inc., Tampa 33612, FL, USA., Hadley E; Department of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles 90089, CA, USA., Costich TL; Intezyne Technologies, Inc., Tampa 33612, FL, USA., Zhou X; Department of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles 90089, CA, USA., Nichols P; Department of Pathology, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles 90089, CA, USA., Lee AS; Department of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles 90089, CA, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 Jul 03; Vol. 9 (51), pp. 29698-29714. Date of Electronic Publication: 2018 Jul 03 (Print Publication: 2018).
DOI:	10.18632/oncotarget.25679
Abstrakt:	In many cancers, combination therapy regimens are successfully improving response and survival rates, but the challenges of toxicity remain. GRP78, the master regulator of the unfolded protein response, is emerging as a target that is upregulated in tumors, specifically following treatment, and one that impacts tumor cell survival and disease recurrence. Here, we show IT-139, an antitumor small molecule inhibitor, suppresses induction of GRP78 from different types of endoplasmic reticulum (ER) stress in a variety of cancer cell lines, including those that have acquired therapeutic resistance, but not in the non-cancer cells being tested. We further determined that IT-139 treatment exacerbates ER stress while at the same time suppresses GRP78 induction at the transcriptional level. Our studies revealed a differential effect of IT-139 on chaperone protein family expression at multiple levels in different cancer cell lines. In xenograft studies, IT-139 decreased BRAF inhibitor upregulation of GRP78 expression in the tumor, while having minimal effect on GRP78 expression in the adjacent normal cells. The preferential decrease in GRP78 levels in tumor cells over normal cells, supported by the manageable safety profile seen in the Phase 1 clinical trial, reinforce the value IT-139 brings to combination therapies as it continues its clinical development. Competing Interests: CONFLICTS OF INTEREST None.
Databáze:	MEDLINE
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