Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

Brazzatti, Julie; Klingler‐Hoffmann, Manuela; Haylock‐Jacobs, Sarah; Harata-Lee, Yuka; Niu, Meizhi; Higgins, Maureen; Kochetkova, Marina; Hoffmann, Peter; McColl, Shaun R.

doi:10.1038/onc.2011.414

Cited by 44 publications

(53 citation statements)

References 68 publications

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“…3). Encoding the γ catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase, PIK3CG has recently been shown to promote breast cancer growth and metastasis (17,18). We verified that knockdown of Mfng caused a dramatic decrease in Pik3cg level, as well as reduced Akt phosphorylation in CLBC cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Manic Fringe Promotes a Claudin-Low Breast Cancer Phenotype through Notch-Mediated PIK3CG Induction

Zhang

Chung

et al. 2015

Cancer Research

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Claudin-low breast cancer (CLBC) is a poor prognosis disease biologically characterized by stemness and mesenchymal features. These tumors disproportionately affect younger patients and women with African ancestry, causing significant morbidity and mortality, and no effective targeted therapy exists at present. CLBC is thought to originate from mammary stem cells, but little is known on how or why these tumors express a stable epithelial-to-mesenchymal transition (EMT) phenotype, or what are the driving forces of this disease. Here we report that Manic Fringe (Mfng), which encodes an O-fucosylpeptide 3-β-N-acetylglucosaminyltransferase known to modify EGF repeats in the Notch extracellular domain, is highly expressed in CLBC and functions as an oncogene in this context. We show that Mfng modulates Notch activation in human and mouse CLBC cell lines, as well as in mouse mammary gland. Mfng silencing in CLBC cell lines reduced cell migration, tumorsphere formation and in vivo tumorigenicity associated with a decrease in the stem-like cell population. Mfng deletion in the Lfngflox/flox; MMTV-Cre mouse model, in which one-third of mammary tumors resemble human CLBC, caused a tumor subtype shift away from CLBC. We identified the phosphoinositide kinase Pik3cg as a direct transcriptional target of Mfng-facilitated RBPJκ-dependent Notch signaling. Indeed, pharmacological inhibition of PI3Kγ in CLBC cell lines blocked migration and tumorsphere formation. Taken together, our results define Mfng as an oncogene acting through Notch-mediated induction of Pik3cg. Further, they suggest that targeting PI3Kγ may prove beneficial for the treatment of claudin-low breast cancer subtype.

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Section: Resultsmentioning

confidence: 99%

Manic Fringe Promotes a Claudin-Low Breast Cancer Phenotype through Notch-Mediated PIK3CG Induction

Zhang

Chung

et al. 2015

Cancer Research

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“…Cell viability assays and calculation of IC 50 were performed using the sulforhodamine B (SRB) cytotoxicity assay as previously described (82).…”

Section: Methodsmentioning

confidence: 99%

“…In regard to cancer, p110γ overexpression can transform chicken embryo fibroblasts in culture via a Ras-dependent mechanism (49). Also, increased PI3Kγ signaling is implicated in the development of breast, pancreatic, and brain tumors or Kaposi sarcoma by promoting tumor inflammation and metastasis (50)(51)(52)(53)(54). Despite the tumorigenic properties of PI3Kγ, Stat1 inhibits cell proliferation and tumorigenesis, suggesting the presence of control pathways mediated by Stat1 to counteract PI3Kγ-mediated tumorigenesis.…”

Section: Stat1 Protects Cells From the Antiproliferative Effects Of Amentioning

confidence: 99%

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Wang

Patsis

Koromilas

2015

Proc. Natl. Acad. Sci. U.S.A.

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The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27Kip1 and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.

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“…Pharmacological inhibition of p110γ can prevent tumor growth and spreading by blocking myeloid-derived tumor inflammation and by suppressing breast cancer cell invasion (8)(9)(10). Depletion of p110γ or its regulatory subunit p101 inhibited primary tumor formation and metastasis by murine epithelial carcinoma cells (11). In pancreatic cancer, it has been proposed that p110γ is an important component of disease progression (12).…”

mentioning

confidence: 99%

Molecular determinants of PI3Kγ-mediated activation downstream of G-protein–coupled receptors (GPCRs)

Vadas

Dbouk²,

Shymanets

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

177

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Phosphoinositide 3-kinase gamma (PI3Kγ) has profound roles downstream of G-protein-coupled receptors in inflammation, cardiac function, and tumor progression. To gain insight into how the enzyme's activity is shaped by association with its p101 adaptor subunit, lipid membranes, and Gβγ heterodimers, we mapped these regulatory interactions using hydrogen-deuterium exchange mass spectrometry. We identify residues in both the p110γ and p101 subunits that contribute critical interactions with Gβγ heterodimers, leading to PI3Kγ activation. Mutating Gβγ-interaction sites of either p110γ or p101 ablates G-protein-coupled receptor-mediated signaling to p110γ/p101 in cells and severely affects chemotaxis and cell transformation induced by PI3Kγ overexpression. Hydrogen-deuterium exchange mass spectrometry shows that association with the p101 regulatory subunit causes substantial protection of the RBD-C2 linker as well as the helical domain of p110γ. Lipid interaction massively exposes that same helical site, which is then stabilized by Gβγ. Membrane-elicited conformational change of the helical domain could help prepare the enzyme for Gβγ binding. Our studies and others identify the helical domain of the class I PI3Ks as a hub for diverse regulatory interactions that include the p101, p87 (also known as p84), and p85 adaptor subunits; Rab5 and Gβγ heterodimers; and the β-adrenergic receptor kinase.

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Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

Cited by 44 publications

References 68 publications

Manic Fringe Promotes a Claudin-Low Breast Cancer Phenotype through Notch-Mediated PIK3CG Induction

Manic Fringe Promotes a Claudin-Low Breast Cancer Phenotype through Notch-Mediated PIK3CG Induction

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Molecular determinants of PI3Kγ-mediated activation downstream of G-protein–coupled receptors (GPCRs)

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