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Molecular and Cellular Biology, August 2007, p. 5499-5513, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.01080-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress{triangledown} ,{dagger}

Mohamed Rahmani, Eric Maynard Davis, Timothy Ryan Crabtree, Joseph Reza Habibi, Tri K. Nguyen, Paul Dent, and Steven Grant*

Departments of Medicine, Biochemistry, and Pharmacology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298

Received 15 June 2006/ Returned for modification 29 September 2006/ Accepted 17 May 2007

Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells. Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2{alpha} (eIF2{alpha}) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [35S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1{alpha} markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1{alpha} or XBP1, disruption of PERK activity, or inhibition of eIF2{alpha} phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.

* Corresponding author. Mailing address: Division of Hematology/Oncology, MCV Station Box 230, Virginia Commonwealth University, Richmond, VA 23298. Phone: (804) 828-5211. Fax: (804) 828-8079. E-mail: stgrant{at}hsc.vcu.edu

{triangledown} Published ahead of print on 4 June 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2007, p. 5499-5513, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.01080-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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