RT Journal Article
SR Electronic
T1 Cystathionine-β-synthase is essential for AKT-induced senescence and suppresses the development of gastric cancers with PI3K/AKT activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.04.451041
DO 10.1101/2021.07.04.451041
A1 Haoran Zhu
A1 Keefe T. Chan
A1 Xinran Huang
A1 Shaun Blake
A1 Anna S. Trigos
A1 Dovile Anderson
A1 Darren Creek
A1 David P. De Souza
A1 Xi Wang
A1 Caiyun Fu
A1 Metta Jana
A1 Elaine Sanij
A1 Richard B Pearson
A1 Jian Kang
YR 2021
UL http://biorxiv.org/content/early/2021/07/04/2021.07.04.451041.abstract
AB 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 increased Cystathionine-β-synthase (CBS) expression and consequent activation of the transsulfuration pathway controlling hydrogen sulfide (H2S) and glutathione (GSH) metabolism. Activated transsulfuration pathway during AIS maintenance enhances the antioxidant capacity, protecting senescent cells from ROS-induced cell death via GSH and H2S. Importantly, CBS depletion allows cells that have undergone AIS to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production and increasing GSH metabolism. These findings implicate a potential tumor-suppressive role for CBS in cells with inappropriately activated PI3K/AKT signaling. Consistent with this concept, in human gastric cancer cells with activated PI3K/AKT signaling, we demonstrate that CBS expression is suppressed due to promoter hypermethylation. CBS loss cooperates with activated PI3K/AKT signaling in promoting anchorage-independent growth of gastric epithelial cells, while CBS restoration suppresses the growth of gastric tumors in vivo. Taken together, we find that CBS is a novel regulator of AIS and a potential tumor suppressor in PI3K/AKT-driven gastric cancers, providing a new exploitable metabolic vulnerability in these cancers.Competing Interest StatementThe authors have declared no competing interest.