S-Glutathionylation and S-Nitrosylation as Modulators of Redox-Dependent Processes in Cancer Cell.

Development of oxidative/nitrosative stress associated with the activation of oncogenic pathways results from the increase in the generation of reactive oxygen and nitrogen species (ROS/RNS) in tumor cells, where they can have a dual effect. At high concentrations, ROS/RNS cause cell death and limit tumor growth at certain phases of its development, while their low amounts promote oxidative/nitrosative modifications of key redox-dependent residues in regulatory proteins. The reversibility of such modifications as S-glutathionylation and S-nitrosylation that proceed through the electrophilic attack of ROS/RNS on nucleophilic Cys residues ensures the redox-dependent switch in the activity of signaling proteins, as well as the ability of these compounds to control cell proliferation and programmed cell death. The content of S-glutathionylated and S-nitrosylated proteins is controlled by the balance between S-glutathionylation/deglutathionylation and S-nitrosylation/denitrosylation, respectively, and depends on the cellular redox status. The extent of S-glutathionylation and S-nitrosylation of protein targets and their ratio largely determine the status and direction of signaling pathways in cancer cells. The review discusses the features of S-glutathionylation and S-nitrosylation reactions and systems that control them in cancer cells, as well as their relationship with redox-dependent processes and tumor growth.

Oxidative Stress and Redox-Dependent Signaling in Prostate Cancer.

Tumor emergence and progression is complicated by the dual role of reactive oxygen species (ROS). Low concentrations of ROS are essential for many intracellular metabolic processes and cell proliferation, while excessive ROS generation disrupts the mechanisms of cancer suppression, leading to the cell damage and death. A long-term imbalance in the ROS/antioxidant ratio and upregulation of the ROS generation due to the reduced efficacy of the antioxidant defense system cause chronic oxidative stress resulting in the damage of proteins, lipid, and DNA molecules and cancer development. Numerous data demonstrate that prostate cancer (the most common cancer in males) is associated with the development of oxidative stress. However, the reasons for the emergence of prostate cancer, as well as changes in the redox signaling and cellular redox homeostasis in this disease, are still poorly understood. The review examines the role of prooxidant and antioxidant enzyme systems, the imbalance in their activity leading to the oxidative stress development, changes in the key components of redox signaling, and the role of microRNAs in the modulation of redox status of cancer cells in prostate cancer.

New Derivatives of Bacteriopurpurin with Thiolated Au (I) Complexes: Dual Darkand Light Activated Antitumor Potency.

BACKGROUND: Conventional antitumor Photosensitizers (PS) are normally low toxic in the dark whereas light activation triggers massive cell death (photodynamic therapy, PDT). OBJECTIVE: To expand the therapeutic potential of PS to dual potency cytocidal agents, taking advantage of the use of bacteriopurpurin for a deeper tissue penetration of light, and suitability of the tetrapyrrolic macrocycle for chemical modifications at its periphery. METHODS: Conjugation of a pro-oxidant thiolate Au (I) moiety to the bacteriopurpurin core and evaluation of cytotoxicity in cell culture and in vivo. RESULTS: New water-soluble derivatives showed micromolar cytotoxicity for cultured human tumor cell lines in the dark, including the subline with an altered drug response due to p53 inactivation. Cellular PDT with the selected conjugate, thiolate Au (I)-dipropoxybacteriopurpurinimide (compound 6) with two triphenylphosphine Au fragments, triggered rapid (within minutes) cell death. Damage to the plasma membrane (necrosis) was a hallmark of cell death by compound 6 both in the dark and upon light activation. Furthermore, one single i.v. injection of compound 6 caused retardation of transplanted syngeneic tumors at the tolerable dose. Illumination of tumors that accumulated compound 6 significantly synergized with the effect of 6 in the dark. CONCLUSION: Complexes of virtually non-toxic, photoactivatable bacteriopurpurin with the gold-containing organic moiety are considered the dual potency antitumor agents, tentatively applicable for intractable tumors.

Intelligent gels and cryogels with entrapped emulsions.

Smart thermoresponsive gels and cryogels with incorporated emulsions have been synthesized and studied. The gels were obtained by three-dimensional copolymerization of N-isopropylacrylamide and N,N'-methylene-bis-acrylamide or N,N'-bis(acryloyl)cystamine in the presence of dispersion of tetradecane stabilized with sodium dodecylsulfate. Polymerization was performed at room temperature and below the water crystallization temperature. Both composite gels and cryogels were capable of heat-induced collapse. The extent of the collapse of the composite gel prepared at room temperature was much smaller and without squeezing of the lipophilic phase out of the shrunk composite gel. In contrast, shrinking of the composite cryogel was accompanied by release of tetradecane emulsion.

Palmitoylation of carboxypeptidase D. Implications for intracellular trafficking.

Covalent lipid modifications mediate protein-membrane and protein-protein interactions and are often essential for function. The purposes of this study were to examine the Cys residues of the transmembrane domain of metallocarboxypeptidase D (CPD) that could be a target for palmitoylation and to clarify the function of this modification. CPD is an integral membrane protein that cycles between the trans Golgi network and the plasma membrane. We constructed AtT-20 cells stably expressing various constructs carrying a reporter protein (albumin) fused to a transmembrane domain and the CPD cytoplasmic tail. Some of the constructs contained the three Cys residues present in the CPD transmembrane region, while other constructs contained Ala in place of the Cys. Constructs carrying Cys residues were palmitoylated, while those constructs lacking the Cys residues were not. Because palmitoylation of several proteins affects their association with cholesterol and sphingolipid-rich membrane domains or caveolae, we tested endogenous CPD and several of the reporter constructs for resistance to extraction with Triton X-100. A construct containing the Cys residues of the CPD transmembrane domain was soluble in Triton X-100 as was endogenous palmitoylated CPD, indicating that palmitoylation does not target CPD to detergent-resistant membrane rafts. Interestingly, constructs of CPD that lack palmitoylation sites have an increased half-life, a slightly more diffuse steady-state localization, and a slower rate of exit from the Golgi as compared with constructs containing palmitoylation sites. Thus, the covalent attachment of palmitic acid to the Cys residues of CPD has a functional significance in the trafficking of the protein.