دورية أكاديمية
BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents.
| العنوان: | BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents. |
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| المؤلفون: | Kanakkanthara A; Department of Oncology, Mayo Clinic, Rochester, Minnesota.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Kurmi K; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Ekstrom TL; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Hou X; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Purfeerst ER; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Heinzen EP; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota., Correia C; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Huntoon CJ; Department of Oncology, Mayo Clinic, Rochester, Minnesota., O'Brien D; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota., Wahner Hendrickson AE; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Dowdy SC; Division of Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota., Li H; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Oberg AL; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota., Hitosugi T; Department of Oncology, Mayo Clinic, Rochester, Minnesota.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Kaufmann SH; Department of Oncology, Mayo Clinic, Rochester, Minnesota.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Weroha SJ; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Karnitz LM; Department of Oncology, Mayo Clinic, Rochester, Minnesota. karnitz.larry@mayo.edu.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota. |
| المصدر: | Cancer research [Cancer Res] 2019 Dec 01; Vol. 79 (23), pp. 5920-5929. Date of Electronic Publication: 2019 Oct 16. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Antineoplastic Combined Chemotherapy Protocols/*pharmacology , BRCA1 Protein/*genetics , Carcinoma, Ovarian Epithelial/*drug therapy , Nicotinamide N-Methyltransferase/*metabolism , Ovarian Neoplasms/*drug therapy, Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; BRCA1 Protein/deficiency ; Carcinoma, Ovarian Epithelial/genetics ; Carcinoma, Ovarian Epithelial/pathology ; Cell Line, Tumor ; Cyclin-Dependent Kinases/genetics ; DNA Methylation ; Energy Metabolism/drug effects ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Hydrazones/pharmacology ; Hydrazones/therapeutic use ; Hydroxybenzoates/pharmacology ; Hydroxybenzoates/therapeutic use ; Mice ; Mitochondria/drug effects ; Mitochondria/metabolism ; Mutation ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Ovary/pathology ; Oxidative Phosphorylation/drug effects ; Promoter Regions, Genetic/genetics ; Tigecycline/pharmacology ; Tigecycline/therapeutic use ; Triazoles/pharmacology ; Triazoles/therapeutic use ; Up-Regulation ; Xenograft Model Antitumor Assays |
| مستخلص: | BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression. SIGNIFICANCE: Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer. (©2019 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | P50 CA136393 United States CA NCI NIH HHS; R01 CA194498 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (BRCA1 Protein) 0 (BRCA1 protein, human) 0 (Hydrazones) 0 (Hydroxybenzoates) 0 (Triazoles) 0 (VLX600) 0 (WZB117) 70JE2N95KR (Tigecycline) EC 2.1.1.1 (NNMT protein, human) EC 2.1.1.1 (Nicotinamide N-Methyltransferase) EC 2.7.11.22 (CDK12 protein, human) EC 2.7.11.22 (Cyclin-Dependent Kinases) |
| تواريخ الأحداث: | Date Created: 20191018 Date Completed: 20200527 Latest Revision: 20200601 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC6891213 |
| DOI: | 10.1158/0008-5472.CAN-19-1405 |
| PMID: | 31619387 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-19-1405 |