Abstract
Abstract Multiple myeloma (MM) patients invariably relapse through mechanisms that remain elusive. Disease recurrence after treatment suggests that rare, tumor-initiating subpopulations with chemoresistant phenotypes persist or emerge to propagate and mediate tumor regrowth. Stem cell-like side population (SP) cells were isolated from myeloma cell lines and patient samples and exhibited resistance to proteasome inhibitors relative to the main population (MP). SP cell-based high-throughput screening detected pharmacologics that enhanced the anti-proliferative effect of bortezomib and revealed the anti-diabetic agent metformin. Bortezomib treatment increased levels of the molecular chaperone glucose-regulated protein GRP78 but metformin co-treatment suppressed bortezomib-induced GRP78 upregulation. Bortezomib treatment also promoted GRP78 co-localization with the signal transducer phosphatidylinositol-3-kinase (PI3K) that activates cell growth and survival pathways. SP cells displayed greater levels of the PI3K product phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and enhanced PI3K-mediated phosphorylation of protein kinase B/AKT compared to MP cells. Metformin treatment or knockdown of GRP78-encoding HSPA5 enhanced sensitivity to bortezomib preferentially in SP cells. Tumor growth was significantly delayed and overall survival prolonged after metformin co-treatment with bortezomib in mice injected with parental or SP cells. Taken together, the results support the pharmacologic repositioning of metformin to inhibit GRP78 induction in therapy-resistant cells and enhance the anti-myeloma benefit of bortezomib. Note: This abstract was not presented at the meeting. Citation Format: James J. Driscoll, Sajjeev Jagannathan, Mohamed AY Abdel Malek, Nikhil Vad, Ehsan Malek. Metformin suppresses GRP78-dependent PI3-Kinase activity in clonogenic side population to enhance the anti-myeloma benefit of bortezomib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4242. doi:10.1158/1538-7445.AM2015-4242
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