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SMS2 suppresses hepatocellular carcinogenesis by impairing p85/p110 interaction

ABSTRACT: Phosphoinositide 3-kinase (PI3K) signaling, which requires spatial compartmentalization in plasma membrane micro domains, is aberrantly activated in hepatocellular carcinoma (HCC). As a synthetic enzyme of sphingomyelin, sphingomyelin synthase 2 (SMS2) regulates membrane fluidity and microdomain structure. SMS2 functions in various diseases such as atherosclerosis, and diabetes and lung injury. However, the role of SMS2 in HCC tumorigenesis is unclear. In the present study, we found that SMS2 was substantially reduced in tumor tissues and predicted poor prognosis in HCC patients. Function assays in vitro showed that SMS2 could remarkably prevent cell proliferation, cell cycle, cell migration and invasion. Experiments in vivo revealed that SMS2-deficient mice exhibited more severe carcinogenesis and metastasis induced by diethylnitrosamine/carbon tetrachloride. The result of transcriptome sequencing showed that SMS2 was involved in PI3K/Akt signaling pathway. Further study verified that SMS2 could inhibit the expression of PI3K subunit p110α by promoting the ubiquitination of p110α. SMS2 downregulation changed lipid metabolism and PTEN distribution in lipid raft, attenuated p85α-PTEN interaction, thus promoting p85α-p110α interaction. Finally, we found that loss of SMS2 could inhibiting PTEN localization in lipid rafts. The tumor suppression effect of SMS2 on HCC cells could be rescued by p110α expression. Taken together, our findings not only demonstrates that SMS2 is a prospective tumor suppressor and prognosis indicator in HCC, but also provide understanding of the molecular mechanisms by which PI3K/AKT signaling is activated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE204898 | GEO | 2023/05/26

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with a 5 year-survival rate below 5%. Lack of curative treatment and failure of targeted therapies urge the need to identify novel efficient therapeutic strategy. Achievement of this goal will be obtained through the identification of diagnosis and prognosis biomarkers, identification of novel therapeutic targets and the knowledge of resistance mechanisms induced by these targeted therapies. PI3K/Akt/mTOR signalling, one of the most altered in cancers, is overactivated in pancreatic cancer and correlated with poor prognosis. In the Vertebrates, the family of class I phosphoinoitide-3-kinase (PI3K) includes four isoforms: p110α, p110β, p110δ and p110γ. Although they all perform the same biochemical reaction (phosphorylation of PIP2 in PIP3, a membrane lipid messenger), each isoform were demonstrated to have specific physiological roles. Global PI3K inhibitors are currently being tested in phase I/II clinical trials in advanced solid cancers, but show at maximal doses tolerated a limited therapeutic benefit. Isoform-selective PI3K inhibitors are currently the most promising agents because, at low doses, they are more efficient to inhibit one PI3K isoform, and thus, less toxic than pan-PI3K inhibitors. The objectives of this thesis are to determine isoform-specific PI3K roles and the therapeutic interest to target one or more isoforms in pancreatitis and PDAC, by the identification of isoform-specific pathways and the study of adaptive responses induced by targeting of one or all isoforms of PI3K. In a first part, my work has highlighted, validated and completed results obtained in the team, to demonstrate the significance of PI3K/Akt signalling in two physiological processes: chronic pancreatitis and initiation of pancreatic carcinogenesis. Precisely, the overactivation of PI3K/Akt pathway measured on human and murine chronic pancreatitis samples is correlated with a specific p110α activation gene expression signature. Moreover, genetic and pharmacologic inactivation of p110α during pancreatic chronic inflammation or cancerogenesis (by oncogenic Kras) prevents the formation of acino-ductal metaplasia, structures at the origin of pancreatic carcinogenesis initiation. Development of in vitro acino-ductal transdifferentiation protocol allowed me to demonstrate that only p110α is necessary at this initial step of pancreatic carcinogenesis by the regulation of Rho small GTPases, further regulating actin remodelling. In the second part, by a phosphoproteomic-based approach, I quantified PI3K downstream phosphorylation-regulated targets in a pancreatic cancer cell line treated or not by a pan- or selective PI3K inhibitor at different times. I demonstrated for the first time existence of targets, signalling pathways and adaptive responses regulated by each PI3K isoform. To conclude, all these results demonstrate the rational of combinatorial use of isoform-specific PI3K inhibitors in patients with pancreatic cancer for better clinical response

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SMS2 suppresses hepatocellular carcinogenesis by impairing p85/p110 interaction

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