P20: Pro- and anti-proliferative effects of hydrogen sulfide in colon cancer cells: A unifying hypothesis

Abstract

Previous studies reported both stimulatory and inhibitory effects of hydrogen sulfide (H2S) donors on the proliferation and viability of in various human cancer cell lines. The aim of this study was to test whether the contradictory data in the literature may be explained by the bell-shaped dose–response character of H2S. Using HCT116 colon cancer cells, proliferation rates were assessed in the presence of different concentrations (0.03–3 mM) of either NaHS (fast-release) or GYY4137 (slow-release) H2S donors, with or without pretreatment with the cystathionine-β-synthase (CBS) inhibitor aminooxyacetic acid (AOAA). In the absence of AOAA, low concentrations (0.03–0.3 mM) of NaHS stimulated proliferation whereas higher concentrations (1–3 mM) inhibited growth. CBS inhibition with AOAA shifted the dose–response to the left, decreasing basal proliferation but also limiting toxicity only to the cells exposed to 3 mM NaHS. In the absence of AOAA, all concentrations of GYY4137 (0.03–3 mM) stimulated HCT116 cell proliferation over the basal growth rate. However, only the highest concentration of GY4137 (3 mM) stimulated HCT116 cells when CBS was inhibited. These data demonstrate that CRC cell proliferation exhibits a biphasic (bell-shaped) dose–response to H2S. The precise nature of the cellular response (increased or decreased growth) is determined by rate H2S production (fast- vs. slow-release H2S donors) as well as the concentration of donor relative to the endogenous (basal) level of CBS-dependent H2S production. Our model provides a useful framework to reconcile some of the controversies in the literature regarding the role of H2S in the regulation of cancer cell proliferation.