Reactive Oxygen and Nitrogen Species–Induced Protein Modifications: Implication in Carcinogenesis and Anticancer Therapy

Abstract

Cancer is a complex disorder extremely dependent on its microenvironment and highly regulated by multiple intracellular and extracellular stimuli. Studies show that reactive oxygen and nitrogen species (RONS) play key roles in cancer initiation and progression. Accumulation of RONS caused by imbalance between RONS generation and activity of antioxidant system (AOS) has been observed in many cancer types. This leads to alterations in gene expression levels, signal transduction pathways, and protein quality control machinery, that is, processes that regulate cancer cell proliferation, migration, invasion, and apoptosis. This review focuses on the latest advancements evidencing that RONS-induced modifications of key redox-sensitive residues in regulatory proteins, that is, cysteine oxidation/Ssulfenylation/S-glutathionylation/S-nitrosylation and tyro-sine nitration, represent important molecular mechanisms underlying carcinogenesis. The oxidative/nitrosative modifications cause alterations in activities of intracellular effectors of MAPK-and PI3K/Akt-mediated signaling pathways, transcription factors (Nrf2, AP-1, NFkB, STAT3, and p53), components of ubiquitin/proteasomal and autophagy/lysosomal protein degradation systems, molecular chaperones, and cytoskeletal proteins. Redox-sensitive proteins, RONSgenerating enzymes, and AOS components can serve as targets for relevant anticancer drugs. Chemotherapeutic agents exert their action via RONS generation and induction of cancer cell apoptosis, while drug resistance associates with RONS-induced cancer cell survival; this is exploited in selective anticancer therapy strategies. Cancer Res; 78(21); 6040-7.

Novel N,N′-Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents

“…Although the connection among reactive oxygen species (ROS) and cancer was suggested in the 1980s [1], in the last years, the scientific community has driven their attention to cellular oxidative stress for treating cancer [2][3][4]. ROS homeostasis is required for normal cell survival and proper cell 2 of 16 signaling, and the excessive production of ROS is considered as an important molecular hallmark for carcinogenesis [5][6][7]. Typically, endogenous radicals usually arise from certain ROS, such as the hydroxyl radical ( − OH), hydrogen peroxide (H 2 O 2 ), the superoxide anion ( • O 2 − ), and singlet oxygen ( 1 O 2 ).…”

Solid‐Phase Synthesis of Substrate‐Based Dipeptides and Heterocyclic Pseudo‐dipeptides as Potential NO Synthase Inhibitors

“…Overproduction of NO is observed in several pathophysiological states and mainly concerns nNOS and iNOS . Neuronal NOS is involved in stroke and neurodegenerative diseases, while iNOS has been identified as the cause of or an aggravating factor in several human diseases involving an inflammatory state, including septic shock, chronic inflammatory diseases, insulin resistance, cancers, migraine .…”

“…[2,[5][6][7] Overproduction of NO is observed in several pathophysiological states and mainly concerns nNOS and iNOS. [8][9][10][11][12] Neuronal NOS is involved in stroke and neurodegenerative diseases, [13,14] while iNOS has been identified as the cause of or an aggravating factor in several human diseases involving an inflammatory state, including septic shock, chronic inflammatory diseases, insulin resistance, cancers, migraine. [15][16][17][18][19][20] Thus, nNOS and iNOS are potential therapeutic targets, but the multiple roles of NO complicate the discovery of inhibitors of pharmaceutical interest.…”

CCDC12 Promotes Tumor Development and Invasion Through the Snail Pathway in Colon Adenocarcinoma

“…translation, ribosomal structure and biogenesis (22); transcription(23); replication, recombination and repair (24); posttranslational modi cation, protein turnover, chaperones (25); and signal transduction mechanisms (26), all of which have been strongly associated with cancer. Cluster analysis divided the differentially expressed proteins into two groups and was in good agreement with the original groups.…”