Role of protein S-Glutathionylation in cancer progression and development of resistance to anti-cancer drugs

The survival, functioning and proliferation of mammalian cells are highly dependent on the cellular response and adaptation to changes in their redox environment. Cancer cells often live in an altered redox environment due to aberrant neo-vasculature, metabolic reprogramming and dysregulated proliferation. Thus, redox adaptations are critical for their survival. Glutathione plays an essential role in maintaining redox homeostasis inside the cells by binding to redox-sensitive cysteine residues in proteins by a process called S-glutathionylation. S-Glutathionylation not only protects the labile cysteine residues from oxidation, but also serves as a sensor of redox status, and acts as a signal for stimulation of downstream processes and adaptive responses to ensure redox equilibrium. The present review aims to provide an updated overview of the role of the unique redox adaptations during carcinogenesis and cancer progression, focusing on their dependence on S-glutathionylation of specific redox-sensitive proteins involved in a wide range of processes including signalling, transcription, structural maintenance, mitochondrial functions, apoptosis and protein recycling. We also provide insights into the role of S-glutathionylation in the development of resistance to chemotherapy. Finally, we provide a strong rationale for the development of redox targeting drugs for treatment of refractory/resistant cancers.