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Extracellular Signal-Regulated Kinase Positively Regulates the Oncogenic Activity of MCT-1 in Diffuse Large B-Cell Lymphoma CANCER RESEARCH Dai, B., Zhao, X. F., Hagner, P., Shapiro, P., Mazan-Mamczarz, K., Zhao, S., Natkunam, Y., Gartenhaus, R. B. 2009; 69 (19): 7835-7843

Abstract

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.

View details for DOI 10.1158/0008-5472.CAN-09-1606

View details for Web of Science ID 000270487600044

View details for PubMedID 19789340

View details for PubMedCentralID PMC2839501