P17 Modulatory effect of S-adenyl-methionine, an allosteric activator of cystathionine-beta-synthase on the proliferation and bioenergetics of colon cancer cells: Mechanism of action

Abstract

Previous studies reported that S-adenosyl- l -methionine (SAM), an allosteric activator of cystathionine-beta-synthase (CBS) increases the production of hydrogen sulfide (H2S) in isolated enzyme preparations. Given the multiple pharmacological effects of SAM, the goal of our study was to probe the specific role of CBS in the effects of SAM in HCT116 colon cancer cells. SAM (0.1 μM–3 mM) concentration-dependently increased CBS-mediated H2S production. The effect of SAM on cell proliferation (assessed real time for up to 24 h by xCELLigence) was time-dependent. SAM (0.1–3 mM) enhanced HCT116 cell proliferation at all concentrations tested in the first 12 h following treatment, but induced cell death/inhibition of proliferation thereafter (12–24 h). The short-term stimulatory effects of SAM were attenuated by stable CBS silencing. In contrast, the anti-proliferative effects of SAM were maintained in cells with CBS silencing. Short-term exposure of HCT116 cells to SAM (0.1–1 mM, 1 h) concentration-dependently increased the oxygen consumption and bioenergetic function of HCT116 cells, while longer-term exposures resulted in a suppression of these parameters at all concentrations of SAM tested. While the stimulatory effect of SAM on proliferation and bioenergetics were attenuated in cells with stable CBS silencing, the inhibitory effects of SAM were largely unaffected by it. Thus, CBS in colon cancer cells produces H2S in a regulated fashion. H2S, when produced at low-to-intermediate levels, serves as an endogenous cancer cell growth and bioenergetic factor. While the short-term inhibition of cell proliferation by high concentrations of SAM may be partially related to “over-stimulation” of CBS, the long-term inhibitory effects of SAM on cell proliferation and bioenergetics are mainly CBS-independent.