FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2978753694> ?p ?o ?g. }

• W2978753694 endingPage "7139" @default.
• W2978753694 startingPage "7122" @default.
• W2978753694 abstract "Background: Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as erlotinib is a major challenge to achieve an overall clinical benefit of the targeted therapy. Recently, aldehyde dehydrogenase 1 (ALDH1) induction has been found to render lung adenocarcinomas resistant to EGFR-TKIs, and targeting ALDH1A1 becomes a novel strategy to overcome resistance. However, the molecular mechanism underlying such effect remains poorly understood. Methods: Comprehensive assays were performed in a panel of lung adenocarcinoma cell lines and xenografts that acquired resistance to erlotinib. Cancer phenotype was evaluated by cell viability, apoptosis, migration, and epithelial-mesenchymal transition analysis in vitro, tumorsphere formation analysis ex vivo, and tumor growth and dissemination analysis in vivo. Reactive oxygen species (ROS) and reactive carbonyl species (RCS) were detected based on fluorescent oxidation indicator and liquid chromatography coupled to mass spectrometry, respectively. Protein target was suppressed by RNA interference and pharmacological inhibition or ecto-overexpressed by lentivirus-based cloning. Gene promoter activity was measured by dual-luciferase reporting assay. Results: Knockdown or pharmacological inhibition of ALDH1A1 overcame erlotinib resistance in vitro and in vivo. ALDH1A1 overexpression was sufficient to induce erlotinib resistance. Metabolomic analysis demonstrated lower ROS-RCS levels in ALDH1A1-addicted, erlotinib-resistant cells; in line with this, key enzymes for metabolizing ROS and RCS, SOD2 and GPX4, respectively, were upregulated in these cells. Knockdown of SOD2 or GPX4 re-sensitized the resistant cells to erlotinib and the effect was abrogated by ROS-RCS scavenging and mimicked by ROS-RCS induction. The ALDH1A1 overexpressed cells, though resisted erlotinib, were more sensitive to SOD2 or GPX4 knockdown. The ALDH1A1 effect on erlotinib resistance was abrogated by ROS-RCS induction and mimicked by ROS-RCS scavenging. Detection of GPX4 and SOD2 expression and analysis of promoter activities of GPX4 and SOD2 under the condition of suppression or overexpression of ALDH1A1 demonstrated that the RCS-ROS-metabolic pathway was controlled by the ALDH1A1-GPX4-SOD2 axis. The ROS-RCS metabolic dependence mechanism in ALDH1A1-induced resistance was confirmed in vivo. Analysis of public databases showed that in patients undergoing chemotherapy, those with high co-expression of ALDH1A1, GPX4, and SOD2 had a lower probability of survival. Conclusions: ALDH1A1 confers erlotinib resistance by facilitating the ROS-RCS metabolic pathway. ALDH1A1-induced upregulation of SOD2 and GPX4, as well as ALDH1A1 itself, mitigated erlotinib-induced oxidative and carbonyl stress, and imparted the TKI resistance. The elucidation of previously unrecognized metabolic mechanism underlying erlotinib resistance provides new insight into the biology of molecular targeted therapies and help to design improved pharmacological strategies to overcome the drug resistance." @default.
• W2978753694 created "2019-10-10" @default.
• W2978753694 creator A5002855077 @default.
• W2978753694 creator A5003642180 @default.
• W2978753694 creator A5023837596 @default.
• W2978753694 creator A5057209439 @default.
• W2978753694 creator A5064765042 @default.
• W2978753694 creator A5069103616 @default.
• W2978753694 creator A5078092925 @default.
• W2978753694 creator A5082888105 @default.
• W2978753694 creator A5083013525 @default.
• W2978753694 creator A5085218636 @default.
• W2978753694 date "2019-01-01" @default.
• W2978753694 modified "2023-10-17" @default.
• W2978753694 title "Aldehyde dehydrogenase 1A1 confers erlotinib resistance via facilitating the reactive oxygen species-reactive carbonyl species metabolic pathway in lung adenocarcinomas" @default.
• W2978753694 cites W1969524738 @default.
• W2978753694 cites W1980763538 @default.
• W2978753694 cites W1994830230 @default.
• W2978753694 cites W1998794592 @default.
• W2978753694 cites W2002490399 @default.
• W2978753694 cites W2005709407 @default.
• W2978753694 cites W2023316892 @default.
• W2978753694 cites W2032206080 @default.
• W2978753694 cites W2037855793 @default.
• W2978753694 cites W2042619042 @default.
• W2978753694 cites W2050946558 @default.
• W2978753694 cites W2051690738 @default.
• W2978753694 cites W2057139407 @default.
• W2978753694 cites W2061029215 @default.
• W2978753694 cites W2068990310 @default.
• W2978753694 cites W2085067380 @default.
• W2978753694 cites W2095190072 @default.
• W2978753694 cites W2103562758 @default.
• W2978753694 cites W2104098330 @default.
• W2978753694 cites W2105504936 @default.
• W2978753694 cites W2106391833 @default.
• W2978753694 cites W2118758371 @default.
• W2978753694 cites W2120245271 @default.
• W2978753694 cites W2120246444 @default.
• W2978753694 cites W2126859620 @default.
• W2978753694 cites W2134029343 @default.
• W2978753694 cites W2135550035 @default.
• W2978753694 cites W2161103689 @default.
• W2978753694 cites W2162188240 @default.
• W2978753694 cites W2214517872 @default.
• W2978753694 cites W2235860151 @default.
• W2978753694 cites W2284683492 @default.
• W2978753694 cites W2336310263 @default.
• W2978753694 cites W2411118623 @default.
• W2978753694 cites W2479121739 @default.
• W2978753694 cites W2517126578 @default.
• W2978753694 cites W2542863264 @default.
• W2978753694 cites W2547320292 @default.
• W2978753694 cites W2586407709 @default.
• W2978753694 cites W2606001457 @default.
• W2978753694 cites W2611545198 @default.
• W2978753694 cites W2611610643 @default.
• W2978753694 cites W2622267958 @default.
• W2978753694 cites W2727828415 @default.
• W2978753694 cites W2736499558 @default.
• W2978753694 cites W2765831845 @default.
• W2978753694 cites W2767055857 @default.
• W2978753694 cites W2793841721 @default.
• W2978753694 cites W2807973331 @default.
• W2978753694 cites W2810028506 @default.
• W2978753694 cites W2888920077 @default.
• W2978753694 cites W2894407493 @default.
• W2978753694 doi "https://doi.org/10.7150/thno.35729" @default.
• W2978753694 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6831290" @default.
• W2978753694 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31695757" @default.
• W2978753694 hasPublicationYear "2019" @default.
• W2978753694 type Work @default.
• W2978753694 sameAs 2978753694 @default.
• W2978753694 citedByCount "35" @default.
• W2978753694 countsByYear W29787536942019 @default.
• W2978753694 countsByYear W29787536942020 @default.
• W2978753694 countsByYear W29787536942021 @default.
• W2978753694 countsByYear W29787536942022 @default.
• W2978753694 countsByYear W29787536942023 @default.
• W2978753694 crossrefType "journal-article" @default.
• W2978753694 hasAuthorship W2978753694A5002855077 @default.
• W2978753694 hasAuthorship W2978753694A5003642180 @default.
• W2978753694 hasAuthorship W2978753694A5023837596 @default.
• W2978753694 hasAuthorship W2978753694A5057209439 @default.
• W2978753694 hasAuthorship W2978753694A5064765042 @default.
• W2978753694 hasAuthorship W2978753694A5069103616 @default.
• W2978753694 hasAuthorship W2978753694A5078092925 @default.
• W2978753694 hasAuthorship W2978753694A5082888105 @default.
• W2978753694 hasAuthorship W2978753694A5083013525 @default.
• W2978753694 hasAuthorship W2978753694A5085218636 @default.
• W2978753694 hasBestOaLocation W29787536941 @default.
• W2978753694 hasConcept C170493617 @default.
• W2978753694 hasConcept C173396325 @default.
• W2978753694 hasConcept C185592680 @default.
• W2978753694 hasConcept C190283241 @default.
• W2978753694 hasConcept C2777930144 @default.
• W2978753694 hasConcept C2778087573 @default.
• W2978753694 hasConcept C2779438470 @default.

• next