A H2S-Nampt Dependent Energetic Circuit Is Critical to Survival and Cytoprotection from Damage in Cancer Cells

Abstract

We recently demonstrated that cancer cells that recover from damage exhibit increased aerobic glycolysis, however, the molecular mechanism by which cancer cells survive the damage and show increased aerobic glycolysis remains unknown. Here, we demonstrate that diverse cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation, and develop tolerance to damage associated with increased production of hydrogen sulfide (H2S) which drives up-regulation of nicotinamide phosphoribosyltransferase (Nampt). Consistent with existence of a H2S-Nampt energetic circuit, in damage recovered cancer cells, H2S, Nampt and ATP production exhibit a significant correlation. Moreover, the treatment of cancer cells with H2S donor, NaHS, coordinately increases Nampt and ATP levels, and protects cells from drug induced damage. Inhibition of cystathionine beta synthase (CBS) or cystathionase (CTH), enzymes which drive generation of H2S, decreases Nampt production while suppression of Nampt pathway by FK866, decreases H2S and ATP levels. Damage recovered cells isolated from tumors grown subcutaneously in athymic mice also show increased production of H2S, Nampt and ATP levels, associated with increased glycolysis and rapid proliferation. Together, these data show that upon recovery from potential lethal damage, H2S-Nampt directs energy expenditure and aerobic glycolysis in cancer cells, leads to their exponential growth, and causes a high degree of tolerance to damage. Identification of H2S-Nampt as a pathway responsible for induction of damage tolerance in cancer cells may underlie resistance to therapy and offers the opportunity to target this pathway as a means in treatment of cancer.

Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential

“…In order for aerobic glycolysis to function and increase production of NADPH, NAD + levels must remain high [49]. Recent evidence has shown that production of H 2 S in other cancers is a crucial component of the aerobic glycolysis energy circuit that reduces oxidative stress and contributes to ATP production by maintaining production of NAD + [31,32]. Therefore, in helping to maintain the supply of NAD + that fuels aerobic glycolysis in ccRCC, H 2 S indirectly ensures that production of the antioxidant NADPH also remains high, resulting in a high XTT assay output even in mitochondria-deficient cells.…”

Regulation and role of endogenously produced hydrogen sulfide in angiogenesis

“…In line with its angiogenic effects and the link between glycolysis and angiogenesis, endogenously produced H 2 S was shown to stimulate the activity of another glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH); GAPDH undergoes S-sulfhydration on the active site cysteine 150 and stimulates glycolytic flux [59, 60]. Although evidence for the contrary (inhibition of GAPDH by H 2 S/persulfidation) has been presented [61], most studies have shown that H 2 S enhances the efficiency of glycolysis in cells [62, 63]. Future studies should aim to quantify the contribution of glycolysis enhancement to the angiogenic actions of H 2 S.…”

Biological signaling by small inorganic molecules

“…Increased H 2 S production from CBS in colorectal and ovarian cancers promotes proliferation, angiogenesis and migration, which can be reversed by silencing of CBS both in vitro and in vivo [337]. Cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation and a nicotinamide phosphoribosyltransferase-dependent increase in tolerance to higher H 2 S levels [338]. Thus treatment of cancer cells with an H 2 S donor protects cells from drug-induced damage [338].…”

“…Cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation and a nicotinamide phosphoribosyltransferase-dependent increase in tolerance to higher H 2 S levels [338]. Thus treatment of cancer cells with an H 2 S donor protects cells from drug-induced damage [338]. Inhibition of CBS may therefore be a potential area for development of anticancer therapeutics [337].…”