CD147 / EMMPRIN mediated cell survival signaling

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4388 CD147 is a widely expressed transmembrane glycoprotein that is upregulated on cancer cells. Over-expression of CD147, a member of the immunoglobulin super-family, promotes invasion, metastasis, and growth and survival of malignant cells. The molecular mechanisms underlying the actions of CD147 are not fully understood. We utilized fibroblast cells from wild-type and CD147 null mice to study signal transduction pathways activated downstream of CD147. When CD147 null fibroblasts were exposed to UV light we observed defective activation of JNK compared to control CD147 expressing fibroblasts. Since CD147 is a cell surface glycoprotein involved in cell-cell interactions and is thought to interact with ligands such as cyclophilins or to interact homotypically or potentially with unknown cell surface proteins on opposing cells, we ligated CD147 with mAb to examine activation of signaling proteins downstream of CD147. We observed that Akt, c-Jun Kinase (JNK), and Erk1/2 are all activated following treatment of CD147 expressing fibroblasts with anti-CD147 mAb OX114. We treated cells with inhibitors of PI3 Kinase (LY294002) and MEK (PD98059) to determine the importance of these signaling pathways in CD147 mediated activation. Inhibition of PI3 Kinase inhibited activation of Akt that follows CD147 ligation, indicating that activation of PI3 Kinase is required for CD147 induced Akt activation. Similarly, c-Jun Kinase activation was greatly decreased by the PI3 Kinase inhibitor. Although the MEK inhibitor did not completely inhibit Erk1/2 activation, it greatly decreased c-Jun Kinase activation indicating that MEK is required for c-Jun Kinase activation downstream of CD147 ligation. Increased expression of CD147 has been suggested to result in enhanced survival of transformed cells. Together with our results of increased Akt, Erk and JNK phosphorylation in response to CD147 ligation, a theme of CD147 promoting a survival signal is emerging. These CD147 signal transduction studies indicate that tumor cell survival may be linked not only to induction of matrix metalloproteinases, but to downstream signaling through CD147 as well.