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Extracellular Signal-Regulated Kinase Positively Regulates the Oncogenic Activity of MCT-1 in Diffuse Large B-Cell Lymphoma

¹ University of Maryland Greenebaum Cancer Center; ² Pathology, University of Maryland School of Medicine; ³ Pharmaceutical Sciences, University of Maryland School of Pharmacy; ⁴ Veterans Administration Medical Center, Baltimore, Maryland; and ⁵ Stanford University School of Medicine, Stanford, California

Requests for reprints: Ronald B. Gartenhaus, The University of Maryland Marlene and Stewart Greenebaum Cancer Center, 9-011 BRB, 655 West Baltimore Street, Baltimore, MD 21201. Phone: 410-328-3691; Fax: 410-328-6559; E-mail: RGartenhaus{at}som.umaryland.edu.

Key Words: Diffuse Large B-Cell Lymphoma • ERK-Signaling • MCT-1 Oncogene

The MCT-1 oncogene was originally identified from lymphoma cell lines. Herein we establish that MCT-1 is highly expressed in 85% of human diffuse large B-cell lymphomas (DLBCL) and that knocking down MCT-1 by a specific short hairpin RNA in DLBCL cells induces apoptosis, supporting a critical role for MCT-1 in DLBCL cell survival. However, the mechanism underlying MCT-1 regulation is largely unknown. We find that MCT-1 is phosphorylated and up-regulated by extracellular signal-regulated kinase (ERK). Furthermore, by using a small inhibitory molecule targeting ERK, we interrupted MCT-1 phosphorylation and stability. Significantly, cells with distinct levels of MCT-1 protein displayed differential sensitivity to ERK inhibitor–induced apoptosis. Treatment with the ERK inhibitor showed marked in vivo antitumor activity in a human DLBCL xenograft model. Our findings establish a functional molecular interaction between MCT-1 and the MEK/ERK signaling pathway and suggest that the activation of MCT-1 function by its upstream kinase ERK plays an important role in lymphomagenesis. [Cancer Res 2009;69(19):7835–43]