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Abstract
The lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti–Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.
Highlights
Galectin-3 (Gal3) is a member of the family of small, highly conserved eukaryotic lectins that recognize specific complex sugars on glycosylated cell surface proteins
We have focused on post-translational modification of the 58 amino acid Mucin 16 (MUC16) “ectodomain” at two proximal N-glycosylation sites, which act as potential drivers of oncogenic behavior[19,20]
We have shown that oncogenic properties of ovarian cancer cell lines are increased by expression of N-glycosylated MUC16 on the cell surface[20]
Summary
Galectin-3 (Gal3) is a member of the family of small, highly conserved eukaryotic lectins that recognize specific complex sugars on glycosylated cell surface proteins. To define the role of Gal[3] in MUC16-dependent cellular activity, our lab previously created Gal[3] knockdown cell lines from MUC16 overexpressing A2780 and SKOV3 cell lines (shLGALS3-A2780 and shLGALS3-SKOV3)[23] These cell lines, with forced expression of the terminal amino acid sequence of the C-terminal MUC16 ectodomain, contain the N-glycosylation sites that drive tumor growth and invasion. In the previously published report, we used a blocking fusion protein engineered by fusing the sugar-binding domain of Gal[3] with a truncated human IgG1 domain. This inhibits Gal[3] pentamerization, which is necessary for its effects on oncogenic signaling. We hypothesized that therapeutic targeting of the Gal[3] carbohydrate-binding domain would downregulate cancer cell invasion and growth
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