Please use this identifier to cite or link to this item:
https://doi.org/10.1038/s41467-017-02287-5
DC Field | Value | |
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dc.title | Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality | |
dc.contributor.author | Kitagawa M. | |
dc.contributor.author | Liao P.-J. | |
dc.contributor.author | Lee K.H. | |
dc.contributor.author | Wong J. | |
dc.contributor.author | Shang S.C. | |
dc.contributor.author | Minami N. | |
dc.contributor.author | Sampetrean O. | |
dc.contributor.author | Saya H. | |
dc.contributor.author | Lingyun D. | |
dc.contributor.author | Prabhu N. | |
dc.contributor.author | Diam G.K. | |
dc.contributor.author | Sobota R. | |
dc.contributor.author | Larsson A. | |
dc.contributor.author | Nordlund P. | |
dc.contributor.author | McCormick F. | |
dc.contributor.author | Ghosh S. | |
dc.contributor.author | Epstein D.M. | |
dc.contributor.author | Dymock B.W. | |
dc.contributor.author | Lee S.H. | |
dc.date.accessioned | 2020-09-06T16:02:58Z | |
dc.date.available | 2020-09-06T16:02:58Z | |
dc.date.issued | 2017 | |
dc.identifier.citation | Kitagawa M., Liao P.-J., Lee K.H., Wong J., Shang S.C., Minami N., Sampetrean O., Saya H., Lingyun D., Prabhu N., Diam G.K., Sobota R., Larsson A., Nordlund P., McCormick F., Ghosh S., Epstein D.M., Dymock B.W., Lee S.H. (2017). Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality. Nature Communications 8 (1) : 2200. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-017-02287-5 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/174480 | |
dc.description.abstract | Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131's ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a RasPI3K signaling network. © 2017 The Author(s). | |
dc.publisher | Nature Publishing Group | |
dc.source | Unpaywall 20200831 | |
dc.subject | a131 | |
dc.subject | antineoplastic agent | |
dc.subject | mammalian target of rapamycin | |
dc.subject | mitogen activated protein kinase | |
dc.subject | phosphatidylinositol 3 kinase | |
dc.subject | phosphatidylinositol 5 phosphate 2 kinase | |
dc.subject | phosphatidylinositol kinase | |
dc.subject | phosphotransferase inhibitor | |
dc.subject | protein kinase B | |
dc.subject | Ras protein | |
dc.subject | unclassified drug | |
dc.subject | membrane protein | |
dc.subject | phosphotransferase | |
dc.subject | PIK3IP1 protein, human | |
dc.subject | protein kinase inhibitor | |
dc.subject | Ras protein | |
dc.subject | cancer | |
dc.subject | cells and cell components | |
dc.subject | enzyme | |
dc.subject | enzyme activity | |
dc.subject | growth | |
dc.subject | inhibition | |
dc.subject | lipid | |
dc.subject | animal experiment | |
dc.subject | animal model | |
dc.subject | animal tissue | |
dc.subject | antineoplastic activity | |
dc.subject | Article | |
dc.subject | breast cancer | |
dc.subject | cancer cell | |
dc.subject | centrosome | |
dc.subject | controlled study | |
dc.subject | enzyme activation | |
dc.subject | female | |
dc.subject | human | |
dc.subject | human cell | |
dc.subject | intracellular signaling | |
dc.subject | lethality | |
dc.subject | mitosis | |
dc.subject | mouse | |
dc.subject | nonhuman | |
dc.subject | upregulation | |
dc.subject | animal | |
dc.subject | antagonists and inhibitors | |
dc.subject | Bagg albino mouse | |
dc.subject | cell proliferation | |
dc.subject | cell survival | |
dc.subject | drug effect | |
dc.subject | drug screening | |
dc.subject | metabolism | |
dc.subject | mitosis | |
dc.subject | neoplasm | |
dc.subject | nude mouse | |
dc.subject | signal transduction | |
dc.subject | tumor cell line | |
dc.subject | Animals | |
dc.subject | Cell Line, Tumor | |
dc.subject | Cell Proliferation | |
dc.subject | Cell Survival | |
dc.subject | Female | |
dc.subject | Humans | |
dc.subject | Membrane Proteins | |
dc.subject | Mice | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Mice, Nude | |
dc.subject | Mitosis | |
dc.subject | Neoplasms | |
dc.subject | Phosphotransferases (Alcohol Group Acceptor) | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | ras Proteins | |
dc.subject | Signal Transduction | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.type | Article | |
dc.contributor.department | DUKE-NUS MEDICAL SCHOOL | |
dc.contributor.department | CANCER SCIENCE INSTITUTE OF SINGAPORE | |
dc.contributor.department | PHARMACY | |
dc.description.doi | 10.1038/s41467-017-02287-5 | |
dc.description.sourcetitle | Nature Communications | |
dc.description.volume | 8 | |
dc.description.issue | 1 | |
dc.description.page | 2200 | |
Appears in Collections: | Elements Staff Publications |
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