Heberle-Razquin Navas-2019 - PI3K-MAPK/p38-mTOR Model V
Ontology highlight
ABSTRACT:
Model V simulating stress induction with stress inputs on PI3K, Akt-pS473 and mTORC1. The model scheme is depicted in Figure S11 and the simulations are shown in Figure S12.
Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours
Project description:Both the PI3K/AKT/mTOR and androgen receptor (AR) signaling pathways play essential roles in prostate cancer. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and apoptosis induction, and observed the strongest effects in androgen-sensitive prostate cancer models. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, with most pronounced effects of the pan-PI3K inhibitor copanlisib. Transcriptomic analysis performed in the androgen-sensitive VCaP cell line revealed that gene expression was more affected by the co-treatment with darolutamide and copanlisib, compared to single agents. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs was observed. The combination treatment also markedly induced DNA damage. An in vivo efficacy study performed using LuCaP 35, an androgen-sensitive patient-derived prostate cancer model, indicated superior efficacy after combined treatment with copanlisib and darolutamide. Immunohistochemistry analysis of treated tumors furthermore showed increased apoptosis. Altogether these data demonstrate that blocking the PI3K/AKT/mTOR and AR pathways with potent inhibitors has superior anti-tumor efficacy and induces apoptosis in androgen-sensitive prostate cancer models.
Project description:To comprehensively analyze the effects of mTORC1 inhibition on GSK3, we employed the use of a PI3K/mTOR-specific phospho-antibody microarray that analyzed the site-specific phosphorylation of over 130 kinases within the PI3K/mTOR pathway. The phosphorylation levels of different kinases in monocytes were measured when stimulated with LPS in the presence or absence of a kind of mTORC1 inhibitor, rapamycin More than 130 highly specific and characterized phospho-antibodies for the human mTOR signaling pathway were immobilized and replicated six times on glass slides. The same non-phosphorylated target antibodies were included to allow the determination of the relative level of phosphorylatioin
Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound.
Project description:To comprehensively analyze the effects of mTORC1 inhibition on GSK3, we employed the use of a PI3K/mTOR-specific phospho-antibody microarray that analyzed the site-specific phosphorylation of over 130 kinases within the PI3K/mTOR pathway. The phosphorylation levels of different kinases in monocytes were measured when stimulated with LPS in the presence or absence of a kind of mTORC1 inhibitor, rapamycin
Project description:The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here we show that MASTL/Greatwall, a cell-cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by expression of phospho-mimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.
Project description:Mucin 3A(MUC3A) is overexpressed in colorectal cancer (CRC) and associated with poor prognosis, but the related mechanism remains unclear. Our study found that MUC3A promotes the progression of CRC by activating the PI3K/Akt/mTOR signaling pathway. Knockout of MUC3A significantly inhibited the proliferation of CRC cells and induced G1 phase arrest by upregulating p21 protein, an important cell cycle regulator. Moreover, knockout of MUC3A significantly inhibited invasion ability and enhanced the sensitivity to the chemotherapeutic agent 5-FU. Furthermore, we found that knockout of MUC3A repressed the PI3K/Akt/mTOR pathway through RNA-seq. Treatment with the PI3K/Akt/mTOR pathway inhibitor rapamycin successfully eliminated the difference in proliferation, invasion and chemoresistance between MUC3A knockout cells and control cells. Our study suggests that MUC3A is a potential oncogene that promotes the proliferation, invasion, and chemotherapy resistance of CRC. Moreover, CRC patients with high expression of MUC3A may benefit from rapamycin treatment.
Project description:IL-7 r and Stat5 signaling drives early B lymphopoiesis, but it remains poorly understood how Stat5-dependent and independent pathways contribute to this process. We report the discrete effects of PI3K and mTOR signaling on Stat5 signaling and B cell development. PI3K was not engaged by IL-7 in pro-B cells but was actively suppressed by PTEN to ensure proper IL-7 r expression, Stat5 signaling and pro-B cell survival. Further, IL-7-mediated mTORC1 activation, which was uncoupled from PI3K signaling, orchestrated a unique program in early B cell development in a Stat5-independent but Myc-dependent manner. mTORC1 was also required for immunoglobulin heavy chain rearrangement and Myc-driven lymphomagenesis. Finally, mTORC2 was not essential for early B cell development but contributed to peripheral B cell maturation. Altogether, genetic dissection of PI3K, mTORC1, and mTORC2 reveals the distinct effects of these seemingly related pathways on B cell development and the intricate interplay between PI3K, mTOR and IL-7 r-Stat5 signaling.
Project description:Alterations of the tumor suppressor TP53, one of the most common events in cancer, alone are insufficient for tumor development but serve as drivers of transformation. We sought to identify cooperating events through genomic analyses of a novel somatic Trp53R245W mouse model (equivalent to the TP53R248W hot spot mutation in human cancers) that recapitulates metastatic breast cancer development. We identified cooperating lesions similar to those found in human breast cancers. Moreover, we identified activation of the Pi3k/Akt/mTOR pathway in most tumors via mutations in Pten, Erbb2, Kras and/or a recurrent Pip5k1c mutation that stabilizes the Pip5k1c protein to activate Pi3k/Akt/mTOR signaling. Another PIP5K1C family member, PIP5K1A, is co-amplified with PI4KB in 18% of human breast cancer patients and both encode kinases that are responsible for production of the PI3K substrate, phosphatidylinositol 4,5-bisphosphate. Thus, the TP53R248W mutation and PI3K/Akt/mTOR signaling are major cooperative events driving breast cancer development. Additionally, we demonstrated that the upregulation of oxidative phosphorylation by Pi3k/Akt/mTOR signaling is a vulnerability in murine as well as human breast cancer cell lines. These findings advance our understanding of mutant p53-driven breast tumors and expand testable targets for breast cancer treatment.
Project description:Hypertrophic scar (HS) is a skin fibroproliferative disease currently having no truly effective therapy. PIK3CA is a catalytic subunit of PI3K able to promote collagen synthesis in benign fibrotic diseases and to regulate cell survival, proliferation, and adhesion in malignancies. To explore PIK3CA’s functions in HS formation, we performed transcriptome sequencing and experimental validation. PIK3CA were overexpressed in HS tissues, and positively correlated with fibrosis. We then screened out miR-203a-3p as the most suitable endogenous inhibitor of PIK3CA through bioinformatics. Intriguingly, miR-203a-3p suppressed the proliferation, migration, collagen synthesis, and contractility, as well as trans-differentiation of fibroblasts into myofibroblasts in vitro, improved the morphology and histology of HS in vivo. Mechanistically, miR-203a-3p attenuated fibrosis by inactivating PI3K/AKT/mTOR pathway via directly targeting PIK3CA. In conclusion, Our findings identified that PIK3CA and PI3K/AKT/mTOR pathway were actively involved in HS formation and demonstrated that miR-203a-3p might serve as a potential strategy for HS therapy through targeting PIK3CA and inactivating PI3K/AKT/mTOR pathway.