Increased demand for FAD synthesis in differentiated and stem pancreatic cancer cells is accomplished by modulating FLAD1 gene expression: the inhibitory effect of Chicago Sky Blue.

Autor: Nisco A; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy., Carvalho TMA; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy., Tolomeo M; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy.; Department of DiBEST (Biologia, Ecologia e Scienze della Terra), University of Calabria, Arcavacata di Rende, Italy., Di Molfetta D; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy., Leone P; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy., Galluccio M; Department of DiBEST (Biologia, Ecologia e Scienze della Terra), University of Calabria, Arcavacata di Rende, Italy., Medina M; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) (GBsC-CSIC Joint Unit), University of Zaragoza, Spain., Indiveri C; Department of DiBEST (Biologia, Ecologia e Scienze della Terra), University of Calabria, Arcavacata di Rende, Italy.; CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), Bari, Italy., Reshkin SJ; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy., Cardone RA; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy., Barile M; Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2023 Oct; Vol. 290 (19), pp. 4679-4694. Date of Electronic Publication: 2023 Jun 07.
DOI: 10.1111/febs.16881
Abstrakt: FLAD1, along with its FAD synthase (FADS, EC 2.7.7.2) product, is crucial for flavin homeostasis and, due to its role in the mitochondrial respiratory chain and nuclear epigenetics, is closely related to cellular metabolism. Therefore, it is not surprising that it could be correlated with cancer. To our knowledge, no previous study has investigated FLAD1 prognostic significance in pancreatic ductal adenocarcinoma (PDAC). Thus, in the present work, the FAD synthesis process was evaluated in two PDAC cell lines: (a) PANC-1- and PANC-1-derived cancer stem cells (CSCs), presenting the R273H mutation in the oncosuppressor p53, and (b) MiaPaca2 and MiaPaca2-derived CSCs, presenting the R248W mutation in p53. As a control, HPDE cells expressing wt-p53 were used. FADS expression/activity increase was found with malignancy and even more with stemness. An increased FAD synthesis rate in cancer cell lines is presumably demanded by the increase in the FAD-dependent lysine demethylase 1 protein amount as well as by the increased expression levels of the flavoprotein subunit of complex II of the mitochondrial respiratory chain, namely succinate dehydrogenase. With the aim of proposing FADS as a novel target for cancer therapy, the inhibitory effect of Chicago Sky Blue on FADS enzymatic activity was tested on the recombinant 6His-hFADS2 (IC 50  = 1.2 μm) and PANC-1-derived CSCs' lysate (IC 50  = 2-10 μm). This molecule was found effective in inhibiting the growth of PANC-1 and even more of its derived CSC line, thus assessing its role as a potential chemotherapeutic drug.
(© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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