Abstract

The proteasome inhibitor Bortezomib (Velcade®) effectively eradicates multiple myeloma (MM) cells, partly by activating endoplasmic reticulum (ER) stress apoptotic signaling. However, MM recurrences in Bortezomib-treated patients are invariable. We have shown that ER stress signaling can also induce growth arrest and survival in cancer cells. Thus, we hypothesized that Bortezomib therapy could induce quiescence and survival of residual MM cells, contributing to disease recurrence. Here we report that in MM cells, proteasome inhibition with MG-132 or Bortezomib results in a surviving cell fraction that enters a prolonged quiescent state (G0-G1 arrest). Mechanism analysis revealed that in Bortezomib-surviving quiescent cells eIF2α phosphorylation and induction of the ER stress pro-apoptotic gene, GADD153, were attenuated. In contrast, p38 and the ER-chaperone BiP/Grp78 were persistently activated and induced, respectively. The Bortezomib-surviving quiescent fraction could be eradicated by a simultaneous or sequential combination therapy with Salubrinal, an inhibitor of GADD34-PP1C phosphatase complex, and in consequence, eIF2α dephosphorylation. This effect was mimicked by expression of a phospho-mimetic eIF2α-S51D mutant. Our data indicate that Bortezomib can induce growth arrest in therapy-surviving MM cells and that attenuation of eIF2α phosphorylation and GADD153 induction contribute to this survival. Most importantly, this ability of MM cells to evade Bortezomib toxicity can be prevented by inhibiting eIF2a dephosphorylation. Thus, strategies that maintain eIF2α in a hyper-phosphorylated state may be a novel therapeutic approach to maximize Bortezomib-induced apoptosis and reduce recurrences in this type of cancer.

Disclosures: No relevant conflicts of interest to declare.

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