|M.Sc Student||Knany Alaa|
|Subject||Characterization of Nitroso-Redox Stress-Induced|
Cancer Cell Death
|Department||Department of Medicine||Supervisor||Professor Moran Benhar|
|Full Thesis text|
Nitric oxide (NO) and its derivatives, known as reactive nitrogen species (RNS), are reactive species that act as endogenous signaling and cytotoxic molecules. Over recent decades, researches have sought ways to harness the cytotoxic potential of NO/RNS for developing effective antitumor therapies. One class of RNS that has drawn considerable recent attention are S-nitrosothiols (SNO), compounds formed by reaction between RNS and thiols. Multiple studies have shown that SNO donors can trigger cancer cell death, by inducing nitrosative stress and/or activating specific cell death pathways. However, effective NO/SNO-based antitumor therapy remains an elusive goal. This is due in part to the challenge posed by redox protective mechanisms employed by tumor cells, in particular the major thiol reducing systems, the glutathione and thioredoxin systems.
Under certain conditions, cancer cells may experience nitroso-redox stress, a condition in which NO/SNO levels are elevated and thiol redox homeostasis is disrupted. The main goal of this work was to characterize in detail molecular and cellular alterations associated with nitroso-redox stress, and to define how this type of stress affects cancer cell viability.
We found that treatment of HeLa cancer cells with l-buthionine-sulfoximine (BSO, a glutathione depleting agent) results in significant sensitization to cell death induced by NO or SNO donors. Mechanistically, combined BSO/SNO treatment leads to rapid and profound inhibition of both glutathione and thioredoxin systems, thereby propagating nitroso-redox imbalance and committing the cells to death. Thiol-redox proteomics identified hundreds of proteins that are preferentially nitrosylated/oxidized in BSO/SNO-treated cells, including key regulators of cell redox, mitochondrial function and cytoskeletal dynamics. Consistently, the early steps in BSO/SNO-induced cell death involve collapse of the actin cytoskeleton and loss of mitochondrial function. Similar to the effects seen in HeLa cells, BSO/SNO combination therapy was effective in killing multiple lung cancer cell lines.
In conclusion, this study provides a unique resource and new insights into cellular-molecular characteristics of nitroso-redox stress and its relationship with cell death pathways. The findings may suggest a possible avenue for improving NO/SNO-based anticancer therapies.