Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, growth and survival of malignant cells, and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that human breast carcinoma cells expressing high levels of EMMPRIN formed aggregates with large surface area, had higher viability, and were resistant to apoptosis in the absence of attachment. Knockdown of EMMPRIN expression by RNA interference (siRNA or shRNA) sensitized those cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a pro-apoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells, and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Inhibition of Bim expression by siRNA decreased the sensitivity to anoikis in cells with low EMMPRIN. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also upregulated Bim accumulation and rendered cells sensitive to anoikis. These results indicate that expression of EMMPRIN protects cancer cells from anoikis, and this effect is mediated by a MAP kinase-dependent reduction of Bim via proteasomal degradation. Since anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]