Disruption of constitutively active Stat3 signaling and myc-mediated glycolysis with the polyphenolic compound resveratrol inhibits proliferation and induces apoptosis in activated B-cell (ABC)-type lymphoma.

A101

ABC-type lymphoma is associated with a 35% five-year survival rate. Although the nuclear factor-kappa B (NF-κB) pathway has been identified as an essential survival signal in ABC-type lymphoma, little is known about signaling mechanisms, which confer oncogenic advantage outside of this pathway. Our interest herein is in elucidating the signal transduction pathway(s) controlling glycolysis, as tumor cells require high rates of glycolytic flux to meet their bioenergetic demands. We found the polyphenolic compound resveratrol inhibits constitutively active Stat3 signaling in the ABC-type lymphoma OCI-LY3. Inhibition of this pathway with the Jak2 inhibitor tyrphostin AG490, resulted in a block in cellular proliferation and subsequent apoptosis. We also found that resveratrol blocked expression of Pim-1 kinase, Mcl-1 and Bcl-xL and c-Myc. Similar results were obtained with tryphostin AG490. Interestingly, resveratrol did not inhibit NF-κB activity as measured by nuclear extract binding to the κB site in the bcl-xL gene promoter. Further, we found inhibition of the Stat3 pathway with either resveratrol or tryphostin AG490 reduced mRNAs encoding several rate-limiting glycolytic enzymes, including phosphofructokinase-1 (PFK-1). Consistent with this finding, resveratrol or tryphostin AG490 reduced glycolytic flux. Taken together, these results suggest the existence of a signaling pathway linking Stat3/Myc to glycolytic metabolism. Moreover, the anti-proliferative action of resveratrol in ABC-type DLBCLs may result from impaired Stat3/Myc signaling to glycolysis. Disruption of this pathway with resveratrol in the poorly responsive ABC-type DLBCL may constitute a novel therapeutic strategy to treat ABC-type DLBCL.