Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy.

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 (G(0)-G(1) arrest). Mechanism analysis revealed that bortezomib-surviving quiescent cells attenuate eIF2alpha phosphorylation and induction of the ER stress

SUBMITTER: Schewe DM 

PROVIDER: S-EPMC2726651 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature