Hydrogen Sulfide Metabolism and Signaling in the Tumor Microenvironment

Hydrogen sulfide (H₂S), 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. H₂S 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 H₂S levels associated with dysfunctional H₂S 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 H₂S-synthesizing enzymes. The resulting increased H₂S 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 H₂S metabolism. Herein are summarized some of the key observations that place H₂S 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 H₂S helps shaping cancer cell bioenergetic metabolism and affords resistance and adaptive mechanisms to hypoxia.