RRC ID 66861
著者 Shen YA, Hong J, Asaka R, Asaka S, Hsu FC, Suryo Rahmanto Y, Jung JG, Chen YW, Yen TT, Tomaszewski A, Zhang C, Attarwala N, DeMarzo AM, Davidson B, Chuang CM, Chen X, Gaillard S, Le A, Shih IM, Wang TL.
タイトル Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers.
ジャーナル Cancer Res
Abstract Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg.
巻・号 80(20)
ページ 4514-4526
公開日 2020-10-15
DOI 10.1158/0008-5472.CAN-19-3971
PII 0008-5472.CAN-19-3971
PMID 32859605
PMC PMC7572606
MeSH Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology Benzeneacetamides / administration & dosage Benzeneacetamides / pharmacology Cell Line, Tumor Cell Survival / drug effects Drug Resistance, Neoplasm / drug effects* Female Gene Expression Regulation, Neoplastic Glutaminase / antagonists & inhibitors Glutaminase / metabolism* Glutamine / genetics Glutamine / metabolism Glutathione / metabolism Humans Mice, Nude Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / genetics Ovarian Neoplasms / metabolism Phthalazines / administration & dosage Phthalazines / pharmacology Piperazines / administration & dosage Piperazines / pharmacology Poly(ADP-ribose) Polymerase Inhibitors / pharmacology Proto-Oncogene Proteins c-myc / genetics Proto-Oncogene Proteins c-myc / metabolism* Thiadiazoles / administration & dosage Thiadiazoles / pharmacology Xenograft Model Antitumor Assays
IF 9.727
リソース情報
ヒト・動物細胞 JHOC-5(RCB1520)