A novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes

@article{Hill2014ANP,
  title={A novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes},
  author={R. Hill and R. Kalathur and S. Callejas and Laura Colaço and Ricardo Brand{\~a}o and Beatriz G. Serelde and A. Cebri{\'a} and C. Blanco-Aparicio and J. Pastor and M. Futschik and A. Dopazo and W. Link},
  journal={Breast Cancer Research : BCR},
  year={2014},
  volume={16}
}
IntroductionThe activation of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is one the most frequent genetic events in breast cancer, consequently the development of PI3K inhibitors has attracted much attention. Here we evaluate the effect of PI3K inhibition on global gene expression in breast cancer cells.MethodsWe used a range of methodologies that include in silico compound analysis, in vitro kinase assays, cell invasion assays, proliferation assays, genome-wide transcription… Expand
Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma.
TLDR
It is shown that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells, and metabolomics as a tool for finding novel therapeutic biomarkers is supported. Expand
Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling
TLDR
The discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator is reported, which shows a potent antiproliferative effect in human cancer cell lines. Expand
NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells.
TLDR
Gene expression and flow cytometry revealed that single and dual treatments induced apoptosis, and stem gene expression was retained in dual NVP-BEZ235/JAKi treatment samples, which indicates that future in vivo studies may give further insight into the impact of combined N VP-BEz 235/Jaki treatment in GBM and BBC. Expand
TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
TLDR
It is reported that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics, and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells. Expand
High-Throughput Image-Based Screening to Identify Chemical Compounds Capable of Activating FOXO.
TLDR
An image-based high-throughput screening platform to detect compounds that regulate FOXO3 subcellular localization and isolate inhibitors of proteins upstream of FOXO, such as PI3K inhibitors is developed. Expand
Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer
TLDR
This study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC models. Expand
microRNA-21 Regulates Cell Proliferation and Migration and Cross Talk with PTEN and p53 in Bladder Cancer.
TLDR
Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that the expression of miR-21 considerably increased in primary cancer tissue compared with that in the paired adjacent noncancerous tissue and that in normal bladder mucosa. Expand
Paclitaxel-resistant cancer cell-derived secretomes elicit ABCB1-associated docetaxel cross-resistance and escape from apoptosis through FOXO3a-driven glycolytic regulation
Chemotherapy-induced cancer cell secretomes promote resistance due, in part, to a predominant glycolytic energy metabolism, which drives aggressive cancer cell proliferation. However, theExpand
FOXO factors and breast cancer: outfoxing endocrine resistance.
TLDR
This review will summarize what is currently known about the role of FOXOs in endocrine-resistance mechanisms and suggest potential therapeutic strategies for the restoration of normal FOXO transcriptional activity. Expand
Tribbles breaking bad: TRIB2 suppresses FOXO and acts as an oncogenic protein in melanoma.
  • W. Link
  • Biology, Medicine
  • Biochemical Society transactions
  • 2015
TLDR
The observation that TRIB2 strongly correlates with the progression of melanocyte-derived malignancies suggestsTRIB2 as a meaningful biomarker to both diagnose and stage melanoma, and interfering with TRIB1 activity might be a therapeutic strategy for the treatment of several different tumour types. Expand
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