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J. Biol. Chem., Vol. 281, Issue 14, 9719-9727, April 7, 2006

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Extracellular Matrix Metalloproteinase Inducer (CD147) Confers Resistance of Breast Cancer Cells to Anoikis through Inhibition of Bim^*

Jin-Ming Yang¹, Peter O'Neill, Wei Jin, Ramsey Foty, Daniel J. Medina, Zude Xu, Mehnaaz Lomas^¶, Greg M. Arndt^¶, Yi Tang^||, Marian Nakada^||, Li Yan^||, and William N. Hait²

From the Departments of Pharmacology, Medicine and Surgery, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, ^||Oncology Research, Centocor, Inc., Malvern, Pennsylvania 19355, and ^¶Johnson & Johnson Research, Level 4, 1 Central Avenue, Eveleigh, New South Wales 1430, Sydney, Australia

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, and 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 in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference (small interfering RNA or short hairpin RNA) sensitized 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 proapoptotic 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. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because 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.

Received for publication, August 1, 2005 , and in revised form, December 23, 2005.

^* This work was supported by Grants NCI CA 66077 and CA 72720 from the United States Public Health Service. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 195 Little Albany St., New Brunswick, NJ 08901. Tel.: 732-235-8075; Fax: 732-235-8094; E-mail: jyang{at}umdnj.edu.

² To whom correspondence may be addressed: The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 195 Little Albany St., New Brunswick, NJ 08901. Tel.: 732-235-8064; Fax: 732-235-8094, E-mail: haitwn{at}umdnj.edu.

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