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Inhibition of ABI2 Ubiquitination-Dependent Degradation Suppresses Breast Cancer Cell Growth via Down-regulating PI3K/Akt Signaling Pathway [RNAseq-20240415]

ABSTRACT: TNBC is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-abi2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2 can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, we also found that the antibiotic Colistimethate could inhibit the growth of TNBC cells by inhibiting CBLC-induced ABI2 ubiquitination and down-regulating PI3K/Akt signaling pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268672 | GEO | 2024/06/04

REPOSITORIES: GEO

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Inhibition of ABI2 Ubiquitination-Dependent Degradation Suppresses Breast Cancer Cell Growth via Down-regulating PI3K/Akt Signaling Pathway [RNAseq-20240420]

Project description:TNBC is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-abi2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2 can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, we also found that the antibiotic Colistimethate could inhibit the growth of TNBC cells by inhibiting CBLC-induced ABI2 ubiquitination and down-regulating PI3K/Akt signaling pathway.

2024-06-04 | GSE268673 | GEO

Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer

Project description:Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide negative selection CRISPR/Cas9 screen with PI3K and AKT inhibitors to identify targetable synthetic lethalities in TNBC. We found that cholesterol homeostasis is a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived organoids of estrogen receptor (ER)-negative breast cancer. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBCs show dysregulated SREBP-2 activation in response to single agent or combination AKT inhibitor and pitavastatin, and this was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss promoted lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. This work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC.

2024-01-14 | GSE252944 | GEO

SOX4 AND SMARCA4 COOPERATIVELY REGULATE PI3K SIGNALING THROUGH TRANSCRIPTIONAL ACTIVATION OF TGFBR2 IN BASAL LIKE BREAST CANCER

Project description:Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.

2021-03-02 | PXD022811 | Pride

SOX4 AND SMARCA4 COOPERATIVELY REGULATE PI3K SIGNALING THROUGH TRANSCRIPTIONAL ACTIVATION OF TGFBR2 IN TRIPLE NEGATIVE BREAST CANCER

2021-03-03 | PXD022596 | Pride

RNAseq of 4T1 cells expressing exogenous LINC01133

Project description:The PI3K pathway represents the most hyperactivated oncogenic pathway in triple-negative breast cancer (TNBC), a highly aggressive tumor subtype encompassing ~15% of breast cancers with no targeted therapeutics. Despite critical contributions of its signaling arms to disease pathogenesis, PI3K pathway inhibitors have not achieved expected clinical responses in TNBC owing largely to still-incomplete understanding of the compensatory cascades that operate downstream of PI3K. Here, we investigated the contributions of long non-coding RNAs (lncRNAs) to PI3K activities in clinical and experimental TNBC, and discovered a prominent role for LINC01133 as a PI3K-AKT signaling effector. We found that LINC01133 exerted pro-tumorigenic roles in TNBC, and that it governed a previously undescribed mTORC2-dependent pathway that activated AKT in a PI3K-independent manner. Mechanistically, we show that LINC01133 induced the expression of the mTORC2 component PROTOR1/PRR5 by competitively coupling away its negative mRNA regulator, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). PROTOR1/PRR5 in turn was sufficient and necessary for LINC01133-triggered functions, casting previously unappreciated roles for this Rictor-binding protein in cellular signaling and growth. Notably, LINC01133 antagonism undermined cellular growth and we show that the LINC01133-PROTOR1/PRR5 pathway tightly associated with TNBC poor patient survival. Altogether, our findings uncovered a lncRNA-driven signaling shunt that acts as a critical determinant of malignancy downstream of the PI3K pathway and as a potential RNA-based theranostic in clinical TNBC management. We performed comparative gene expression profiling analyses using RNA-seq of triplicates of control 4T1 cells (harboring empty plasmid control) and 4T1 cell trioplicates expressing exogenous LINC01133.

2022-10-03 | GSE212004 | GEO

C2 skeletal myotube phosphoproteome

Project description:Skeletal muscle is known to adapt dynamically to changes in workload by regulatory processes of the phosphatidylinositide 3-kinase (PI3K)/Akt pathway. We performed a global quantitative phosphoproteomics analysis of contracting mouse C2 myotubes treated with insulin growth factor 1 (IGF-1) or LY294002 to activate or inhibit PI3K/Akt signaling, respectively.

2020-05-25 | PXD009117 | Pride

FOXO3a Is A Major Target Of Inactivation By PI3K/AKT Signaling In Aggressive Neuroblastoma

Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.

2013-05-01 | E-GEOD-42762 | biostudies-arrayexpress

SMS2 suppresses hepatocellular carcinogenesis by impairing p85/p110 interaction

Project description: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.

2023-05-26 | GSE204898 | GEO

IGF-1 stimulated C2 skeletal myotube phosphoproteome

Project description:Skeletal muscle is known to adapt dynamically to changes in workload by regulatory processes of the phosphatidylinositide 3-kinase (PI3K)/Akt pathway. We performed a global quantitative phosphoproteomics analysis of contracting mouse C2 myotubes treated with insulin growth factor 1 (IGF-1) as control and additionally MK-2206 or LY294002 to inhibit PI3K/Akt signaling, respectively.

2020-05-25 | PXD016721 | Pride

Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Project description:Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity.

2022-10-28 | PXD034117 | Pride

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