Hypoxic resistance of KRAS mutant tumor cells to 3-Bromopyruvate is counteracted by Prima-1 and reversed by N-acetylcysteineReport as inadecuate




Hypoxic resistance of KRAS mutant tumor cells to 3-Bromopyruvate is counteracted by Prima-1 and reversed by N-acetylcysteine - Download this document for free, or read online. Document in PDF available to download.

BMC Cancer

, 16:902

Cell and molecular biology

Abstract

BackgroundThe metabolic inhibitor 3-bromopyruvate 3-BrPA is a promising anti-cancer alkylating agent, shown to inhibit growth of some colorectal carcinoma with KRAS mutation. Recently, we demonstrated increased resistance to 3-BrPA in wt p53 tumor cells compared to those with p53 silencing or mutation. Since hypoxic microenvironments select for tumor cells with diminished therapeutic response, we investigated whether hypoxia unequally increases resistance to 3-BrPA in wt p53 MelJuso melanoma harbouring Q61L-mutant NRAS and wt BRAF, C8161 melanoma with G12D-mutant KRAS G464E-mutant BRAF, and A549 lung carcinoma with a KRAS G12S-mutation. Since hypoxia increases the toxicity of the p53 activator, Prima-1 against breast cancer cells irrespective of their p53 status, we also investigated whether Prima-1 reversed hypoxic resistance to 3-BrPA.

ResultsIn contrast to the high susceptibility of hypoxic mutant NRAS MelJuso cells to 3-BrPA or Prima-1, KRAS mutant C8161 and A549 cells revealed hypoxic resistance to 3-BrPA counteracted by Prima-1. In A549 cells, Prima-1 increased p21CDKN1mRNA, and reciprocally inhibited mRNA expression of the SLC2A1-GLUT1 glucose transporter-1 and ALDH1A1, gene linked to detoxification and stem cell properties. 3-BrPA lowered CAIX and VEGF mRNA expression. Death from joint Prima-1 and 3-BrPA treatment in KRAS mutant A549 and C8161 cells seemed mediated by potentiating oxidative stress, since it was antagonized by the anti-oxidant and glutathione precursor N-acetylcysteine.

ConclusionsThis report is the first to show that Prima-1 kills hypoxic wt p53 KRAS-mutant cells resistant to 3-BrPA, partly by decreasing GLUT-1 expression and exacerbating pro-oxidant stress.

KeywordsHypoxia ALDH1A1 GLUT1 p53 reactivation KRAS mutation Abbreviations3-BrPA3-bromopyruvate

CAIXCarbonic anhydrase 9

ROSReactive oxygen species

SLC2A1-GLUT1Glucose transporter 1

VEGFVascular endothelial growth factor.

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Author: Andrea Orue - Valery Chavez - Mary Strasberg-Rieber - Manuel Rieber

Source: https://link.springer.com/







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