Transport and transporters in the endoplasmic reticulum

Enzyme activities localized in the luminal compartment of the endoplasmic reticulum are integrated into the cellular metabolism by transmembrane fluxes of their substrates, products and/or cofactors. Most compounds involved are bulky, polar or even charged; hence, they cannot be expected to diffuse through lipid bilayers. Accordingly, transport processes investigated so far have been found protein-mediated. The selective and often rate-limiting transport processes greatly influence the activity, kinetic features and substrate specificity of the corresponding luminal enzymes. Therefore, the phenomenological characterization of endoplasmic reticulum transport contributes largely to the understanding of the metabolic functions of this organelle. Attempts to identify the transporter proteins have only been successful in a few cases, but recent development in molecular biology promises a better progress in this field.     

Inhibitors of arachidonic acid metabolism act synergistically to signal apoptosis in neoplastic cells

Arachidonic acid (AA) and its metabolites are intimately linked to carcinogenesis. Inhibitors of AA metabolic enzymes have demonstrated anti-carcinogenic effects in vivo and induce apoptosis of many cancer cell lines in vitro. The mechanism by which AA influences carcinogenesis, however, remains unresolved. The current study explores the growth inhibitory potential of Triacsin C, PLT-98625, and NS-398 which inhibit three distinct metabolic enzymes that control intracellular AA levels: fatty acid coenzyme-A ligase 4 (FACL-4), coenzyme-A independent transacylase (CoA-IT), and cyclooxygenase (COX), respectively. Results reveal the anti-proliferative effects of these inhibitors in a number of human cancer cell lines. Further studies in the SK-MES-1 cell line demonstrate that all three inhibitors induce accumulation of unesterified AA which correlates with induction of apoptosis. Addition of exogenous AA also induces apoptosis. Furthermore, in combination, these inhibitors act cooperatively to induce AA accumulation which correlates to a synergistic reduction in cell viability. Taken together, these results suggest that accumulation of unesterified AA is a common mechanism in the induction of cancer cell apoptosis by various inhibitors of AA metabolism, confirm that previously described AA remodeling pathways are valid in cancer cells, and indicate that combination treatment strategies utilizing these inhibitors may represent a novel approach to blocking cancer cell growth. Further study is required to determine the downstream pathway(s) whereby high cellular burdens of unesterified AA promote apoptosis.