Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis

Abstract

Cancer metastasis and immune suppression are critical issues in cancer therapy. Here, we show that a β-galactoside-binding lectin [galectin-3 (gal3)] that recognizes the Thomsen-Friedenreich disaccharide (TFD, Galβ1,3GalNAc) present on the surface of most cancer cells is involved in promoting angiogenesis, tumor-endothelial cell adhesion, and metastasis of prostate cancer cells, as well as evading immune surveillance through killing of activated T cells. To block gal3-mediated interactions, we purified a glycopeptide from cod (designated TFD 100 ) that binds gal3 with picomolar affinity. TFD 100 blocks gal3-mediated angiogenesis, tumor-endothelial cell interactions, and metastasis of prostate cancer cells in mice at nanomolar levels. Moreover, apoptosis of activated T cells induced by either recombinant gal3 or prostate cancer patient serum-associated gal3 was inhibited at nanomolar concentration of TFD 100 . Because the gal3-TFD interaction is a key factor driving metastasis in most epithelial cancers, this high-affinity TFD 100 should be a promising antimetastatic agent for the treatment of various cancers, including prostate adenocarcinoma.antifreeze glycoprotein | PC3-luciferase cells | galectin-3 knockout PC3-luciferase cells | TF antigen | surface plasmon resonance

Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3

“…As galectin-3 was involved in tumor cell migration and metastasis [13–16], we evaluated the expression of galectin-3 in breast tissue specimens from cancer patients who smoked or never smoked by immunostaining with anti-galectin-3 antibody [31]. Expression of galectin-3 was significantly increased in a stage-dependent manner in both smokers (p<0.001) and non-smokers (p<0.05) (Fig.…”

“…Galectin-3, a member of at least fifteen β-galactoside-binding soluble lectins family is involved in tumor cell adhesion, angiogenesis, cancer progression and metastasis [13–16]. Galectin-3 expression in gastric, liver, lung, bladder, and head and neck cancers was significantly increased compared to the normal tissues, and correlated with the progression of clinical stages and formation of metastases [17–20].…”

“…Resistance to apoptosis is not only essential for cancer cell survival but also for tumor progression. Conversely, secreted galectin-3 from tumor cell induces T-cell apoptosis implicating a possible role in immune escape mechanism during tumor progression [16, 23]. Several recent studies highlighted the clinical and biological significance of increased galectin-3 expression in apoptosis resistance in cancer cells in connection to targeted cancer therapies and also documented therapeutic effects of synthetic carbohydrate-based small molecule inhibitors of galectin-3 (26–29).…”

Endothelial integrin α3β1 stabilizes carbohydrate-mediated tumor/endothelial cell adhesion and induces macromolecular signaling complex formation at the endothelial cell membrane

“…Recently, yet another group used natural TF-Ag expressing glycopeptide TFD100 isolated from Atlantic cod to inhibit TF-Ag/Gal-3 mediated tumor/endothelial cell adhesion and ultimately PC-3 metastasis in vivo [31]. Inhibiting simultaneously additional subsequent steps of tumor metastasis mediated by endothelial integrins will increase dramatically our ability to control hematogenous spread of cancer.…”

Tumor-released Galectin-3, a Soluble Inhibitory Ligand of Human NKp30, Plays an Important Role in Tumor Escape from NK Cell Attack

“…Moreover, GCS-100, a polysaccharide that may detach Gal-3 from tumorinfiltrating lymphocytes, boosted cytotoxicity and the secretion of IFN-␥, leading to tumor rejection in mice (17). Recently, Guha et al (18) found that TFD100, a glycopeptide from cod that binds Gal-3 with picomolar affinity, inhibited the apoptosis of activated T cells following induction with either recombinant Gal-3 or prostate cancer patient serum-associated Gal-3 at nanomolar concentrations. Collectively, Gal-3 may work as an immune regulator to induce apoptosis in activated T cells.…”