4 years ago

Antibodies Against Specific MUC16 Glycosylation Sites Inhibit Ovarian Cancer Growth

Antibodies Against Specific MUC16 Glycosylation Sites Inhibit Ovarian Cancer Growth
Sahityasri Thapi, Alberto Fernández-Tejada, Kay J. Park, Nestor Rosales, Douglas A. Levine, Narciso Olvera, Jason S. Lewis, Amy Wang, Xiujun Yan, David R. Spriggs, Abram Axelrod, Jingyi Xiang, Brandon Nemieboka, Samuel J. Danishefsky, Thapi Dharma Rao
Expression of the retained C-terminal extracellular portion of the ovarian cancer glycoprotein MUC16 induces transformation and tumor growth. However, the mechanisms of MUC16 oncogenesis related to glycosylation are not clearly defined. We establish that MUC16 oncogenic effects are mediated through MGAT5-dependent N-glycosylation of two specific asparagine sites within its 58 amino acid ectodomain. Oncogenic signaling from the C-terminal portion of MUC16 requires the presence of Galectin-3 and growth factor receptors colocalized on lipid rafts. These effects are blocked upon loss of either Galectin-3 expression or activity MGAT5. Using synthetic MUC16 glycopeptides, we developed novel N-glycosylation site directed monoclonal antibodies that block Galectin-3-mediated MUC16 interactions with cell surface signaling molecules. These antibodies inhibit invasion of ovarian cancer cells, directly blocking the in vivo growth of MUC16-bearing ovarian cancer xenografts, elucidating new therapeutic modalities.

Publisher URL: http://dx.doi.org/10.1021/acschembio.7b00305

DOI: 10.1021/acschembio.7b00305

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