![how to escape full screen mode mendeley. how to escape full screen mode mendeley.](https://img.extrememanual.net/2018/06/win10_escape_safe_mode_black_screen_02.jpg)
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. 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. 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. These findings implicate a potential tumor-suppressive role for CBS in cells with aberrant PI3K/AKT pathway activation. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production by reducing mitochondrial localized CBS while retaining antioxidant capacity of transsulfuration pathway. CBS depletion allows AIS cells to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. 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 (H 2S) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. 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. Department of Biochemistry and Molecular Biology, University of Melbourne, Australia.Department of Medicine, St Vincent’s Hospital, University of Melbourne, Australia.Department of Biochemistry and Molecular Biology, Monash University, Australia.Department of Clinical Pathology, University of Melbourne, Australia.St Vincent’s Institute of Medical Research, Australia.Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, China.Department of Oncology, The People’s Liberation Army No.Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, Australia.Monash Institute of Pharmaceutical Sciences, Australia.
![how to escape full screen mode mendeley. how to escape full screen mode mendeley.](https://i.stack.imgur.com/4WHJg.png)
Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia.Division of Cancer Research, Peter MacCallum Cancer Centre, Australia.