Disrupted expression of CXCL5 in colorectal cancer is associated with rapid tumor formation in rats and poor prognosis in patients.

Purpose: We isolated a subline (CC531M) from the CC531S rat colon carcinoma cell line, which grows and metastasizes much more rapidly than CC531S. We found, using RNA expression profiling, that one of the major changes in the CC531M cell line was a 5.8-fold reduction of the chemokine CXCL5.

The deubiquitinating enzyme UCH-L3 regulates the apical membrane recycling of the epithelial sodium channel.

The epithelial sodium channel (ENaC) is ubiquitinated by the E3 ligase Nedd4-2 at the apical membranes of polarized cortical collecting duct (CCD) epithelial cells. This leads to ENaC endocytosis and possible degradation. Because ENaC is known to recycle at the apical membranes of CCD cells, deubiquitinating enzymes (DUBs) are likely involved in regulating ENaC surface density by facilitating ENaC recycling as opposed to degradation.

Peptide-bond modified glutathione conjugate analogs modulate GSTpi function in GSH-conjugation, drug sensitivity and JNK signaling.

Glutathione S-transferase pi (GST, E.C.2.

Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation.

An increased expression of focal adhesion kinase (FAK) in a variety of cancers is associated with a poor disease prognosis. To study the role of FAK in breast tumor growth and metastasis formation, we used conditional doxycycline-regulated expression of a dominant-negative acting splice variant of FAK, FAK-related non-kinase (FRNK), in MTLn3 mammary adenocarcinoma cells in a syngeneic Fischer 344 rat tumor and metastasis model. In cell culture, doxycycline-mediated expression of FRNK inhibited MTLn3 cell spreading and migration in association with reduced formation of focal adhesions and phosphorylation of FAK on Tyr(397), but FRNK did not cause apoptosis.

Glutathione conjugates and their synthetic derivatives as inhibitors of glutathione-dependent enzymes involved in cancer and drug resistance.

Alterations in levels of glutathione (GSH) and glutathione-dependent enzymes have been implicated in cancer and multidrug resistance of tumor cells. The activity of a number of these, the multidrug resistance-associated protein 1, glutathione S-transferase, DNA-dependent protein kinase, glyoxalase I, and gamma-glutamyl transpeptidase, can be inhibited by GSH-conjugates and synthetic analogs thereof. In this review we focus on the function of these enzymes and carriers in cancer and anti-cancer drug resistance, in relation to their inhibition by GSH-conjugate analogs.

Inhibition of the multidrug resistance protein 1 (MRP1) by peptidomimetic glutathione-conjugate analogs.

Inhibition of multidrug resistance protein 1 (MRP1) mediated cytostatic drug efflux might be useful in the treatment of drug resistant tumors. Because the glutathione (GSH) conjugate of ethacrynic acid (EA), GS-EA, is a good substrate of MRP1, GS-EA derivatives are expected to be good inhibitors of MRP1. To study structure-activity relationships of MRP1 inhibition, a series of novel GS-EA analogs was synthesized in which peptide bonds of the GSH backbone were replaced by isosteric groups [Bioorg Med Chem 10:195-205, 2002].

Inhibition of glutathione S-transferase in rat hepatocytes by a glycine-tetrazole modified S-alkyl-GSH analogue.

Glutathione (GSH) conjugates inhibit enzymes that are involved in drug metabolism and drug resistance, but their cellular uptake is very low. To improve membrane-permeability, we synthesized a novel GSH-conjugate analogue with a tetrazole carboxylate isostere at the glycine position. Introduction of the tetrazole decreases inhibitory potency towards CDNB conjugation by glutathione S-transferase.

Peptidomimetic glutathione analogues as novel gammaGT stable GST inhibitors.

Elevated levels of glutathione-S-transferase (GST) isoenzymes are found in many tumor cells and are thought to play a role in the onset of multidrug resistance (MDR). To evaluate the contribution of GST to this process, inhibitors are needed. Glutathione (GSH) conjugates, although good GST inhibitors, cannot be used in vivo, because they are eliminated rapidly.