Hydrogen Sulfide Metabolism and Signaling in the Tumor Microenvironment.

Hydrogen sulfide (HS), while historically perceived merely as a toxicant, has progressively emerged as a key regulator of numerous processes in mammalian physiology, exerting its signaling function essentially through interaction with and/or modification of proteins, targeting mainly cysteine residues and metal centers. As a gaseous signaling molecule that freely diffuses across aqueous and hydrophobic biological milieu, it has been designated the third 'gasotransmitter' in mammalian physiology. HS is synthesized and detoxified by specialized endogenous enzymes that operate under a tight regulation, ensuring homeostatic levels of this otherwise toxic molecule. Indeed, imbalances in HS levels associated with dysfunctional HS metabolism have been growingly correlated with various human pathologies, from cardiovascular and neurodegenerative diseases to cancer. Several cancer cell lines and specimens have been shown to naturally overexpress one or more of the HS-synthesizing enzymes. The resulting increased HS levels have been proposed to promote cancer development through the regulation of various cancer-related processes, which led to the interest in pharmacological targeting of HS metabolism. Herein are summarized some of the key observations that place HS metabolism and signaling pathways at the forefront of the cellular mechanisms that support the establishment and development of a tumor within its complex and challenging microenvironment. Special emphasis is given to the mechanisms whereby HS helps shaping cancer cell bioenergetic metabolism and affords resistance and adaptive mechanisms to hypoxia.