Rebollido-Rios, Rocio ORCID: 0000-0002-8910-867X, Venton, Geoffroy, Sanchez-Redondo, Sara, Iglesias i Felip, Carmela, Fournet, Guy, Gonzalez, Elena, Fernandez, Wilber Romero, Escuela, Dasiel Oscar Borroto, Di Stefano, Barbara, Penarroche-Diaz, Reinier, Martin, Guillaume, Ceylan, Ismail, Costello, Regis and Perez-Alea, Mileidys (2020). Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer. Oncogene, 39 (13). S. 2756 - 2772. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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Abstract

Aldehyde dehydrogenases (ALDHs) are multifunctional enzymes that oxidize diverse endogenous and exogenous aldehydes. We conducted a meta-analysis based on The Cancer Genome Atlas and Gene Expression Omnibus data and detected genetic alterations in ALDH1A1, ALDH1A3, or ALDH3A1, 86% of which were gene amplification or mRNA upregulation, in 31% of nonsmall cell lung cancers (NSCLCs). The expression of these isoenzymes impacted chemoresistance and shortened survival times in patients. We hypothesized that these enzymes provide an oxidative advantage for the persistence of NSCLC. To test this hypothesis, we used genetic and pharmacological approaches with DIMATE, an irreversible inhibitor of ALDH1/3. DIMATE showed cytotoxicity in 73% of NSCLC cell lines tested and demonstrated antitumor activity in orthotopic xenografts via hydroxynonenal-protein adduct accumulation, GSTO1-mediated depletion of glutathione and increased H2O2. Consistent with this result, ALDH1/3 disruption synergized with ROS-inducing agents or glutathione synthesis inhibitors to trigger cell death. In lung cancer xenografts with high to moderate cisplatin resistance, combination treatment with DIMATE promoted strong synergistic responses with tumor regression. These results indicate that NSCLCs with increased expression of ALDH1A1, ALDH1A3, or ALDH3A1 may be targeted by strategies involving inhibitors of these isoenzymes as monotherapy or in combination with chemotherapy to overcome patient-specific drug resistance.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rebollido-Rios, RocioUNSPECIFIEDorcid.org/0000-0002-8910-867XUNSPECIFIED
Venton, GeoffroyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Redondo, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iglesias i Felip, CarmelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fournet, GuyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez, Wilber RomeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Escuela, Dasiel Oscar BorrotoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Stefano, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Penarroche-Diaz, ReinierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, GuillaumeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceylan, IsmailUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Costello, RegisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Alea, MileidysUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-345633
DOI: 10.1038/s41388-020-1184-9
Journal or Publication Title: Oncogene
Volume: 39
Number: 13
Page Range: S. 2756 - 2772
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5594
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
STEM-CELLS; EXPRESSION; MECHANISM; 1A1; INHIBITORS; MARKER; APOPTOSIS; SUBSTRATE; REDUCTASE; ALDH1A3Multiple languages
Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34563

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