Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway
| Autor: | Bingbing Dai, Jason B. Fleming, David Roife, Jithesh J. Augustine, Michael P. Kim, Lin Tan, John N. Weinstein, Ya'an Kang, Philip L. Lorenzi, Jenying Deng, Xinqun Li, Leona Rusling |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Elongation Factor 2 Kinase Cancer Research NF-E2-Related Factor 2 Immunology Asparagine synthetase Antineoplastic Agents Apoptosis Synthetic lethality Mice SCID Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine In vivo Mice Inbred NOD Pancreatic cancer Cell Line Tumor medicine NAD(P)H Dehydrogenase (Quinone) Animals Humans Asparagine Gastrointestinal diseases Cell Proliferation QH573-671 Chemistry Drug discovery Aspartate-Ammonia Ligase Cell Biology medicine.disease Xenograft Model Antitumor Assays Tumor Burden Pancreatic Neoplasms 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Cancer research Cytology Ex vivo |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 7, Pp 1-11 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Nuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P 50) of NSLC01 and NQO1 expression was confirmed (r = −0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P n = 7–8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers. |
| Databáze: | OpenAIRE |
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