YWHAE/14-3-3ε expression impacts the protein load contributing to proteasome inhibitor sensitivity in multiple myeloma.

High protein load is a feature of multiple myeloma (MM), making the disease exquisitely sensitive to proteasome inhibitor (PI). Despite success of PI improving patient outcome, majority of patients develop resistance leading to progressive disease; thus, the need to investigate the mechanisms driving the drug sensitivity vs. resistance. With the well-recognized chaperon function of 14-3-3 proteins, we evaluated their role in impacting proteasome activity and sensitivity to PIs by correlating expression of individual 14-3-3 gene and their sensitivity to PIs (bortezomib and carfilzomib) across a large panel of MM cell lines. We observed a significant positive correlation between 14-3-3ε expression with PIs response. We observed a positive function for 14-3-3ε in promoting translation initiation and protein synthesis in MM cells through binding and inhibition of the TSC1/TSC2 complex as well as directly interacting and promoting phosphorylation of mTORC1. 14-3-3ε depletion caused up to 50% reduction in protein synthesis, including decrease in the intracellular abundance and secretion of the light chains in MM cells, whereas 14-3-3ε overexpression or addback in KO cells resulted in a marked upregulation of protein synthesis and protein load. Importantly, the correlation between 14-3-3ε expression, PIs sensitivity and protein load was observed in primary MM cells from two independent datasets; and its lower expression was associated with poor outcome in MM patients receiving a bortezomib-based therapy. Altogether these observations suggest that 14-3-3ε is a predictor of clinical outcome and may serve as a potential target to modulate PIs sensitivity in MM.

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