Sugarcoating ER Stress.

The hexosamine biosynthetic pathway (HBP) generates metabolites for protein N- and O-glycosylation. Wang et al. and Denzel et al. report a hitherto unknown link between the HBP and stress in the endoplasmic reticulum. These studies establish the HBP as a critical component of the cellular machinery of protein homeostasis.

Synthesis of bivalent lactosides and their activity as sensors for differences between lectins in inter- and intrafamily comparisons.

The synthesis of nine bivalent lactosides (based on ditriazoles, diamides, a glycocyclophane and an acyclic analogue of the glycocyclophane) and one monovalent lactosyl triazole facilitated the assessment of the sensitivity of plant/animal lectins to this type of ligand display. The inhibitory potency of the compounds was determined in two assays of increasing biorelevance. These were solid-phase and cell binding set-ups. Hereby, the ability of the compounds to inhibit the binding of two plant agglutinins and the entire set of adhesion/growth-regulatory galectins from one organism (chicken) to a glycoprotein or to cell surfaces was systematically evaluated. Differential sensitivities were detected between plant and animal lectins and also between distinct galectin forms within the chicken series. Two of the bivalent probes can be considered as sensors for interlectin differences. Most pronounced were the selectivities of N-glycosyl 1,2,3-triazole derivatives for the chimera-type galectin and its proteolytically truncated version.

Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma.

Multiple myeloma is characterized by the malignant proliferating antibody-producing plasma cells in the bone marrow. Despite recent advances in therapy that improve the survival of patients, multiple myeloma remains incurable and therapy resistance is the major factor causing lethality. Clearly, more effective treatments are necessary. In recent years it has become apparent that, as highly secretory antibody-producing cells, multiple myeloma cells require an increased capacity to cope with unfolded proteins and are particularly sensitive to compounds targeting proteostasis such as proteasome inhibitors, which represent one of the most prominent new therapeutic strategies. Because of the increased requirement for dealing with secretory proteins within the endoplasmic reticulum, multiple myeloma cells are heavily reliant for survival on a set of signaling pathways, known as the unfolded protein response (UPR). Thus, directly targeting the UPR emerges as a new promising therapeutic strategy. Here, we provide an overview of the current understanding of the UPR signaling in cancer, and outline its important role in myeloma pathogenesis and treatment. We discuss new therapeutic approaches based on targeting the protein quality control machinery and particularly the IRE1α/XBP1 axis of the UPR.