Vitamin C-induced breast cancer cell death is associated with remodeling the redox state of cysteine-containing proteins involved in translation and cell cycle progression

ABSTRACT: Recent studies show vitamin C (VitC) pro-oxidant properties at high pharmacological concentrations which favor repurposing VitC as an anti-cancer therapeutic agent. However, redox-based anticancer properties of different forms of VitC are yet partially understood. We examined the difference between the reduced and oxidized forms of VitC, ascorbic acid (AA) and dehydroascorbic acid (DHA), in terms of cytotoxicity and redox mechanisms toward breast cancer cells. Our data showed that AA displays higher cytotoxicity towards triple-negative breast cancer (TNBC) cell lines in vitro than DHA. AA has a similar cytotoxicity on non-TNBC breast cancer cells with much less effect on noncancerous cell lines. Using MDA-MB-231, a representative TNBC cell line, we observed that cellular redox-state alterations conditioned AA- and DHA-induced cytotoxicity. Hydrogen peroxide (H2O2) accumulation extracellularly and in different intracellular compartments, and to a less degree, induced intracellular GSH oxidation, played a key role in AA-induced cytotoxicity. In contrast, DHA affected GSH oxidation and thus had less cytotoxicity. Furthermore, different cytotoxicity is observed among breast cancer cell lines. Bioinformatics analysis and biological experiments showed that peroxiredoxin 1 (PRDX1) expression levels correlates with AA differential cytotoxicity in breast cancer cells. A “redoxome” proteomics approach revealed that AA treatment altered the redox state of key antioxidant enzymes (PRDX 1-3) and a number of cysteines-containing proteins including many nucleic acid binding proteins and proteins involved in RNA, DNA and energetic processes. We showed that cell cycle progression delay and translation inhibition are parts of the underlying mechanisms for AA-induced cytotoxicity.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Breast Cancer

SUBMITTER: Thibaut LEGER  

LAB HEAD: Meng-Er Huang

PROVIDER: PXD013833 | Pride | 2019-08-16

REPOSITORIES: Pride