A novel role of sONE/NOS3/NO signaling cascade in mediating hydrogen sulphide bilateral effects on triple negative breast cancer progression

Hydrogen sulphide (H2S) gas has been recognized as an intracellular mediator influencing an array of signaling pathways. Yet, the role of H2S in cancer progression has been controversial. This study aims to unravel the role of exogenous H2S in triple negative breast cancer (TNBC) and to further investigate any possible association of H2S mediated actions with the endogenous production of nitric oxide (NO) gas. A wide concentration range of NaHS (20-2000 NM) and a variable reaction time (2-72 h) were probed. A bell-shaped impact of H2S on TNBC cellular viability, proliferation, migration, invasion and colony forming ability was repeatedly observed in the aggressive TNBC cell lines, MDA-MB-231 but not in hormone receptor positive, MCF-7 cells. This bell-shaped effect was found to be shifted towards the left upon increasing the reaction time within the range of 2-24 h. However, this was totally opposed in case of continuous exposure (72 h) to exogenous H2S. An inverted bell-shaped effect of H2S on TNBC cellular growth, migration, proliferation and colony forming ability was shown. Moreover, this study provided the first evidence of a possible involvement of NO in mediating H2S actions in TNBC. Such intricate cross-talk was found to be orchestrated by the novel lncRNA, BONE and its down-stream target NOS3 building up a novel axis, BONE/NOS3/NO, that was shown to play a pivotal role in plotting the bilateral effect of H2S on TNBC progression. Finally, this study showed that low and continuous exposure of H2S serves as a novel, selective and effective strategy in harnessing TNBC oncogenic profile through cGMP dependent and independent pathways where alterations of cell cycle regulatory proteins such as TP53 and c-Myc was observed. Moreover, NaHS could repress TNBC migration and invasion capacities through repressing the intracellular adhesion molecule, ICAM-1. In conclusion, this study provides an insight about the role of exogenous H2S in TNBC cell lines highlighting a novel crosstalk between H2S and NO orchestrated by sONE/NOS3 axis.