This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-3858v1 69/4/1545    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schewe, D. M. Articles by Aguirre-Ghiso, J. A. Search for Related Content PubMed PubMed Citation Articles by Schewe, D. M. Articles by Aguirre-Ghiso, J. A.

Inhibition of eIF2 Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy

Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Julio A. Aguirre-Ghiso, Department of Medicine, Division of Hematology and Oncology, Box 1079, One Gustave L. Levy Place, New York, NY 10029. Phone: 212-241-9582; Fax: 212-996-5787; E-mail: julio.aguirre-ghiso{at}mssm.edu.

Key Words: multiple myeloma • growth arrest • proteasome inhibitor • p38 • salubrinal

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 bortezomib-surviving quiescent cells attenuate eIF2 phosphorylation and induction of the ER stress proapoptotic gene GADD153. This occurs independently of the eIF2 upstream kinases PERK, GCN2, and PKR. In contrast, the prosurvival ER-chaperone BiP/Grp78 was persistently induced. 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, eIF2 dephosphorylation. This effect was mimicked by expression of a phosphorylated mimetic eIF2-S51D mutant. Our data indicate that bortezomib can induce growth arrest in therapy-surviving MM cells and that attenuation of eIF2 phosphorylation contributes to this survival. Most importantly, this survival mechanism can be blocked by inhibiting eIF2 dephosphorylation. Thus, strategies that maintain eIF2 in a hyperphosphorylated state may be a novel therapeutic approach to maximize bortezomib-induced apoptosis and reduce residual disease and recurrences in this type of cancer. [Cancer Res 2009;69(4):1545–52]

This article has been cited by other articles:

				F. Parlati, S. J. Lee, M. Aujay, E. Suzuki, K. Levitsky, J. B. Lorens, D. R. Micklem, P. Ruurs, C. Sylvain, Y. Lu, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome Blood, October 15, 2009; 114(16): 3439 - 3447. [Abstract] [Full Text] [PDF]