Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells
| Autor: | Fumi Higuchi, Daniel P. Cahill, Seamus Rafferty, Julie J. Miller, Lisa Melamed, Hiroaki Wakimoto, Christine K. Lee, Kensuke Tateishi, Megha Subramanian, Hiroaki Nagashima |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Glycoside Hydrolases Nicotinamide adenine dinucleotide Cofactor Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Tumor Cells Cultured Humans Cytotoxicity Poly(ADP-ribose) glycohydrolase Antineoplastic Agents Alkylating chemistry.chemical_classification PARG biology Glioma NAD Isocitrate Dehydrogenase 030104 developmental biology Enzyme Oncology chemistry Biochemistry 030220 oncology & carcinogenesis Cancer cell Mutation biology.protein NAD+ kinase |
| Zdroj: | Cancer Discov |
| Popis: | NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation. Significance: Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit. See related commentary by Pirozzi and Yan, p. 1629. This article is highlighted in the In This Issue feature, p. 1611 |
| Databáze: | OpenAIRE |
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