Targeting SET/I(2)PP2A Oncoprotein Functions as a Multi-pathway Strategy for Cancer Therapy

The SET oncoprotein participates in cancer progression by affecting multiple cellular processes, inhibiting the tumor suppressor PP2A and inhibiting the metastasis suppressor nm23-H1. Based upon these multiple activities, we hypothesized that targeted inhibition of SET would have multiple discrete and measurable effects on cancer cells. Here, the effects of inhibiting SET oncoprotein function on intracellular signaling and proliferation of human cancer cell lines was investigated. We observed the effects of COG112, a novel SET interacting peptide, on PP2A activity, Akt signaling, nm23-H1 activity, and cellular migration/invasion in human U87 glioblastoma and MDA-MB-231 breast adenocarcinoma cancer cell lines. We found that COG112 interacted with SET protein and inhibited the association between SET and PP2A-c or nm23-H1. The interaction between COG112 and SET caused PP2A phosphatase, and nm23-H1 exonuclease activities, to increase. COG112-mediated increases in PP2A activity resulted in the inhibition of Akt signaling and cellular proliferation. Additionally, COG112 inhibited SET association with Rac1 leading to decreased cellular migration and invasion. COG112 treatment releases the SET-mediated inhibition of the tumor suppressor PP2A, as well as the metastasis suppressor nm23-H1. These results establish SET as a novel molecular target, and that the inhibition of SET may have beneficial effects in cancer chemotherapy.