The pro-inflammatory cytokines IL-1β and IL-6 promote upregulation of the ST6GAL1 sialyltransferase in pancreatic cancer cells.

The ST6GAL1 sialyltransferase is overexpressed in multiple cancers, including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an α2-6-linked sialic acid to N-glycosylated membrane receptors, which consequently modulates receptor structure and function. While many studies have investigated the effects of ST6GAL1 on cell phenotype, there is a dearth of knowledge regarding mechanisms that regulate ST6GAL1 expression.

ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression.

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that ST6 β-galactoside α2,6 sialyltransferase 1 (ST6GAL1), which adds α2,6-linked sialic acids to N-glycosylated proteins, was upregulated in patients with early-stage PDAC and was further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft experiments with human PDAC cells.

Upregulated ethanolamine phospholipid synthesis via selenoprotein I is required for effective metabolic reprogramming during T cell activation.

Objective: T cell activation triggers metabolic reprogramming to meet increased demands for energy and metabolites required for cellular proliferation. Ethanolamine phospholipid synthesis has emerged as a regulator of metabolic shifts in stem cells and cancer cells, which led us to investigate its potential role during T cell activation.

Methods: As selenoprotein I (SELENOI) is an enzyme participating in two metabolic pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, we generated SELENOI-deficient mouse models to determine loss-of-function effects on metabolic reprogramming during T cell activation.

Regulation of ST6GAL1 sialyltransferase expression in cancer cells.

The ST6GAL1 sialyltransferase, which adds α2-6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics.

Targeting the C-terminus of galectin-9 induces mesothelioma apoptosis and M2 macrophage depletion.

Galectin-9 has emerged as a promising biological target for cancer immunotherapy due to its role as a regulator of macrophage and T-cell differentiation. In addition, its expression in tumor cells modulates tumor cell adhesion, metastasis, and apoptosis. Malignant mesothelioma (MM) is an aggressive neoplasm of the mesothelial cells lining the pleural and peritoneal cavities, and in this study, we found that both human MM tissues and mouse MM cells express high levels of galectin-9.

Molecular Mechanisms by Which Selenoprotein K Regulates Immunity and Cancer.

Many of the 25 members of the selenoprotein family function as enzymes that utilize their selenocysteine (Sec) residues to catalyze redox-based reactions. However, some selenoproteins likely do not exert enzymatic activity by themselves and selenoprotein K (SELENOK) is one such selenoprotein family member that uses its Sec residue in an alternative manner. SELENOK is an endoplasmic reticulum (ER) transmembrane protein that has been shown to be important for ER stress and for calcium-dependent signaling.

Correction: Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis.

[This corrects the article DOI: 10.18632/oncotarget.24388.

Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis.

Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca flux for disease progression. We investigated the effects of deleting Selenoprotein K (SELENOK) in melanoma since previous work in immune cells showed SELENOK was required for efficient Ca flux through the endoplasmic reticulum Ca channel protein, inositol 1,4,5-trisphosphate receptor (IP3R), which is due to the role SELENOK plays in palmitoylating and stabilizing the expression of IP3R. CRISPR/Cas9 was used to generate SELENOK-deficiency in human melanoma cells and this led to reduced Ca flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration.

Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme.

Calpain-2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain-2 inhibitor therapy reduced inflammation-driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain-2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage-independent growth for all cell five lines. When tested for levels of calpain-2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher).

Selenoproteins and Metastasis.

Cancer survival is largely impacted by the dissemination of cancer cells from the original tumor site to secondary tissues or organs through metastasis. Targets for antimetastatic therapies have recently become a focus of research, but progress will require a better understanding of the molecular mechanisms driving metastasis. Selenoproteins play important roles in many of the cellular activities underlying metastasis including cell adhesion, matrix degradation and migration, invasion into the blood and extravasation into secondary tissues, and subsequent proliferation into metastatic tumors along with the angiogenesis required for growth.