Dataset Information

Targeting SHIP1 and SHIP2 in Cancer.

ABSTRACT: Membrane-anchored and soluble inositol phospholipid species are critical mediators of intracellular cell signaling cascades. Alterations in their normal production or degradation are implicated in the pathology of a number of disorders including cancer and pro-inflammatory conditions. The SH2-containing 5' inositol phosphatases, SHIP1 and SHIP2, play a fundamental role in these processes by depleting PI(3,4,5)P₃, but also by producing PI(3,4)P₂ at the inner leaflet of the plasma membrane. With the intent of targeting SHIP1 or SHIP2 selectively, or both paralogs simultaneously, small molecule inhibitors and agonists have been developed and tested in vitro and in vivo over the last decade in various disease models. These studies have shown promising results in various pre-clinical models of disease including cancer and tumor immunotherapy. In this review the potential use of SHIP inhibitors in cancer is discussed with particular attention to the molecular structure, binding site and efficacy of these SHIP inhibitors.

SUBMITTER: Pedicone C

PROVIDER: S-EPMC7924360 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting SHIP1 and SHIP2 in Cancer.

Pedicone Chiara C Meyer Shea T ST Chisholm John D JD Kerr William G WG

Cancers 20210220 4

Membrane-anchored and soluble inositol phospholipid species are critical mediators of intracellular cell signaling cascades. Alterations in their normal production or degradation are implicated in the pathology of a number of disorders including cancer and pro-inflammatory conditions. The SH2-containing 5' inositol phosphatases, SHIP1 and SHIP2, play a fundamental role in these processes by depleting PI(3,4,5)P<sub>3</sub>, but also by producing PI(3,4)P<sub>2</sub> at the inner leaflet of the p ...[more]

PMID: 33672717

Similar Datasets

Project description:Evidence suggests that various forms of ?-synuclein- (?Syn-) mediated microglial activation are associated with the progression of Parkinson's disease. MicroRNA-155-5p (miR155-5p) is one of the most important microRNAs and enables a robust inflammatory response. Triptolide (T10) is a natural anti-inflammatory component, isolated from a traditional Chinese herb. The objective of the current study was to identify the role and potential regulatory mechanism of T10 in ?Syn-induced microglial activation via the miR155-5p mediated SHIP1 signaling pathway. Mouse primary microglia were exposed to monomers, oligomers, and preformed fibrils (PFFs) of human wild-type ?Syn, respectively. The expressions of TNF? and IL-1?, measured by enzyme-linked immunosorbent assay (ELISA) and qPCR, demonstrated that PFFs initiated the strongest immunogenicity in microglia. Application of inhibitors of toll-like receptor (TLR) 1/2, TLR4, and TLR9 indicated that PFFs activated microglia mainly via the NF-?B pathway by binding TLR1/2 and TLR4. Treatment with T10 significantly suppressed PFF-induced microglial activation and attenuated the release of proinflammatory cytokines including TNF? and IL-1?. Levels of IRAK1, TRAF6, IKK?/?, p-IKK?/?, NF-?B, p-NF-?B, PI3K, p-PI3K, t-Akt, p-Akt and SHIP1 were measured via Western blot. Levels of miR155-5p were measured by qPCR. The results demonstrated that SHIP1 acted as a downstream target molecule of miR155-5p. Treatment with T10 did not alter the expression of IRAK1 and TRAF6, but significantly decreased the expression of miR155-5p, resulting in upregulation of SHIP1 and repression of NF-?B activity, suggesting inhibition of inflammation and microglial activation. The protective effects of T10 were abolished by the use of SHIP1 siRNA and its inhibitor, 3AC, and miR155-5p mimics. In conclusion, our results demonstrated that treatment with T10 suppressed microglial activation and attenuated the release of proinflammatory cytokines by suppressing NF-?B activity via targeting the miR155-5p/SHIP1 pathway in PFFs-induced microglial activation.

Project description:BackgroundProhibitin 2 (PHB2) exhibits opposite functions of promoting or inhibiting tumour across various cancer types. In this study, we aim to investigate its functions and underlying mechanisms in the context of gastric cancer (GC).MethodsPHB2 protein expression levels in GC and normal tissues were examined using western blot and immunohistochemistry. PHB2 expression level associations with patient outcomes were examined through Kaplan-Meier plotter analysis utilizing GEO datasets (GSE14210 and GSE29272). The biological role of PHB2 and its subsequent regulatory mechanisms were elucidated in vitro and in vivo. GC cell viability and proliferation were assessed using MTT cell viability analysis, clonogenic assays, and BrdU incorporation assays, while the growth of GC xenografted tumours was measured via IHC staining of Ki67. The interaction among PHB2 and SHIP2, as well as between SHIP2 and NEDD4, was identified through co-immunoprecipitation, GST pull-down assays, and deletion-mapping experiments. SHIP2 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis.ResultsOur analysis revealed a substantial increase in PHB2 expression in GC tissues compared to adjacent normal tissues. Notably, higher PHB2 levels correlated with poorer patient outcomes, suggesting its clinical relevance. Functionally, silencing PHB2 in GC cells significantly reduced cell proliferation and retarded GC tumour growth, whereas overexpression of PHB2 further enhanced GC cell proliferation. Mechanistically, PHB2 physically interacted with Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) in the cytoplasm of GC cells, thus leading to SHIP2 degradation via its novel E3 ligase NEDD4. It subsequently activated the PI3K/Akt signaling pathway and thus promoted GC cell proliferation.ConclusionsOur findings highlight the importance of PHB2 upregulation in driving GC progression and its association with adverse patient outcomes. Understanding the functional impact of PHB2 on GC growth contributes valuable insights into the molecular underpinnings of GC and may pave the way for the development of targeted therapies to improve patient outcomes.

Dataset Information

Targeting SHIP1 and SHIP2 in Cancer.

Publications

Targeting SHIP1 and SHIP2 in Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets