Cystathionine-β-synthase is essential for AKT-induced senescence and suppresses the development of gastric cancers with PI3K/AKT activation.

Hyperactivation of oncogenic pathways downstream of RAS and PI3K/AKT in normal cells induces a senescence-like phenotype that acts as a tumor-suppressive mechanism that must be overcome during transformation. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. Here, we demonstrate that human fibroblasts undergoing AIS display upregulated cystathionine-β-synthase (CBS) expression and enhanced uptake of exogenous cysteine, which lead to increased hydrogen sulfide (HS) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death.

Oncogene-induced senescence: From biology to therapy.

Oncogene-induced senescence (OIS) is a powerful intrinsic tumor-suppressive mechanism, arresting cell cycle progression upon oncogene-activating genomic alterations. The discovery and characterization of the senescence-associated secretome unveiled a rich additional complexity to the senescence phenotype, including extrinsic impacts on the microenvironment and engagement of the immune response. Emerging evidence suggests that senescence phenotypes vary depending on the oncogenic stimulus.

A functional genetic screen defines the AKT-induced senescence signaling network.

Exquisite regulation of PI3K/AKT/mTORC1 signaling is essential for homeostatic control of cell growth, proliferation, and survival. Aberrant activation of this signaling network is an early driver of many sporadic human cancers. Paradoxically, sustained hyperactivation of the PI3K/AKT/mTORC1 pathway in nontransformed cells results in cellular senescence, which is a tumor-suppressive mechanism that must be overcome to promote malignant transformation.

Cystathionine -Synthase in Physiology and Cancer.

Cystathionine -synthase (CBS) regulates homocysteine metabolism and contributes to hydrogen sulfide (HS) biosynthesis through which it plays multifunctional roles in the regulation of cellular energetics, redox status, DNA methylation, and protein modification. Inactivating mutations in CBS contribute to the pathogenesis of the autosomal recessive disease CBS-deficient homocystinuria. Recent studies demonstrating that CBS promotes colon and ovarian cancer growth in preclinical models highlight a newly identified oncogenic role for CBS.