دورية أكاديمية
أعرض في EDS

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase.

التفاصيل البيبلوغرافية
العنوان: PIK3CA mutant tumors depend on oxoglutarate dehydrogenase.
المؤلفون: Ilic N; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Birsoy K; Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY 10065., Aguirre AJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Kory N; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.; Whitehead Institute for Biomedical Research, Cambridge, MA 02142.; David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139., Pacold ME; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.; Whitehead Institute for Biomedical Research, Cambridge, MA 02142.; David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139., Singh S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Moody SE; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., DeAngelo JD; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Spardy NA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Freinkman E; Whitehead Institute for Biomedical Research, Cambridge, MA 02142., Weir BA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Tsherniak A; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Cowley GS; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Root DE; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Asara JM; Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115., Vazquez F; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142., Widlund HR; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Sabatini DM; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.; Whitehead Institute for Biomedical Research, Cambridge, MA 02142.; David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139., Hahn WC; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; william_hahn@dfci.harvard.edu.; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
المصدر: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Apr 25; Vol. 114 (17), pp. E3434-E3443. Date of Electronic Publication: 2017 Apr 10.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Class I Phosphatidylinositol 3-Kinases*/genetics , Class I Phosphatidylinositol 3-Kinases*/metabolism , Ketoglutarate Dehydrogenase Complex*/biosynthesis , Ketoglutarate Dehydrogenase Complex*/genetics , Mutation* , Neoplasm Proteins*/genetics , Neoplasm Proteins*/metabolism , Neoplasms*/enzymology , Neoplasms*/genetics , Neoplasms*/pathology, Animals ; Cell Line, Tumor ; Citric Acid Cycle/genetics ; Glycolysis/genetics ; Humans ; Mice ; Mice, Nude
مستخلص: Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.
Competing Interests: Conflict of interest statement: W.C.H. is a consultant for Novartis.
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معلومات مُعتمدة: K22 CA193660 United States CA NCI NIH HHS; U01 CA199253 United States CA NCI NIH HHS; United States HHMI Howard Hughes Medical Institute; P01 CA120964 United States CA NCI NIH HHS; P01 CA142536 United States CA NCI NIH HHS; R01 CA130988 United States CA NCI NIH HHS; U01 CA176058 United States CA NCI NIH HHS; U54 CA112962 United States CA NCI NIH HHS; UL1 TR001102 United States TR NCATS NIH HHS; P30 CA006516 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: 2OG; OGDH; PIK3CA; TCA cycle; glycolysis
المشرفين على المادة: 0 (Neoplasm Proteins)
EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex)
EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
EC 2.7.1.137 (PIK3CA protein, human)
تواريخ الأحداث: Date Created: 20170412 Date Completed: 20180423 Latest Revision: 20181113
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC5410781
DOI: 10.1073/pnas.1617922114
PMID: 28396387
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.1617922114