Fig. 12.
The various roles of H2S in the stimulation of EMT in cancer cells. H2S can stimulate Wnt/β-catenin pathway through: Sp3 transcription factor upregulation that, in turn, upregulate ACLY. ACLY interacts with β-catenin and may block β-catenin ubiquitination leading to its accumulation in the cytoplasm which, in turn, also translocates into the nucleus. In the nucleus, β-catenin binds to LEF and activates Twist1 and Snail1 transcription factors. H2S can stimulate PI3K/Akt pathway, which upregulates HIF1α, or induces Snail1 transcription factors expression through NF-κB. H2S can also stimulate the MEK/ERK pathway, leading to the activation of the transcription factor AP1. H2S can stimulate TGFβ pathway through: Smad2/3 activation, which, in turn, activates the transcription factor Snail1. H2S can stimulate p38MAPK pathway, either by activation of the upstream kinases MKKx which consequently phosphorylate p38MAPK or by the autophosphorylation of p38MAPK. Under hypoxic conditions H2S can induce HIF-1α expression and further up-regulate VEGFA and the transcription factor Twist1. Some of these pathways are interconnected and can be activated at the same time. Possible crosstalks between these pathways are indicated by brown arrows. The bell-shaped effect H2S should be emphasized in the above processes, meaning that these pathways can be upregulated during EMT in cancer cells, however this process can be reverted if additional H2S is added to the cells or if the H2S biosynthesis is inhibited in cancer cells. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)