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Cystathionine-ß-synthase is essential for AKT-induced senescence and suppresses the development of gastric cancers with PI3K/AKT activation.
Zhu, Haoran; Chan, Keefe T; Huang, Xinran; Cerra, Carmelo; Blake, Shaun; Trigos, Anna S; Anderson, Dovile; Creek, Darren J; De Souza, David P; Wang, Xi; Fu, Caiyun; Jana, Metta; Sanij, Elaine; Pearson, Richard B; Kang, Jian.
Afiliação
  • Zhu H; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Chan KT; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
  • Huang X; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Cerra C; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
  • Blake S; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Trigos AS; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
  • Anderson D; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Creek DJ; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • De Souza DP; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Wang X; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
  • Fu C; Monash Institute of Pharmaceutical Sciences, Victoria, Australia.
  • Jana M; Monash Institute of Pharmaceutical Sciences, Victoria, Australia.
  • Sanij E; Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, Victoria, Australia.
  • Pearson RB; Department of Oncology, The People's Liberation Army No. 903rd Hospital, Hangzhou, China.
  • Kang J; Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
Elife ; 112022 06 27.
Article em En | MEDLINE | ID: mdl-35758651
ABSTRACT
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-ß-synthase (CBS) expression and enhanced uptake of exogenous cysteine, which lead to increased hydrogen sulfide (H2S) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death. CBS depletion allows AIS cells 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 by reducing mitochondrial localized CBS while retaining antioxidant capacity of transsulfuration pathway. These findings implicate a potential tumor-suppressive role for CBS in cells with aberrant PI3K/AKT pathway activation. 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.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Sulfeto de Hidrogênio Limite: Humans Idioma: En Revista: Elife Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Austrália

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Sulfeto de Hidrogênio Limite: Humans Idioma: En Revista: Elife Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Austrália