Retrograde response to mitochondrial dysfunctions associated to LOF variations in <i>FLAD1</i> exon 2: unraveling the importance of RFVT2

Tolomeo, Maria; Chimienti, Guglielmina; Lanza, Martina; Barbaro, Roberto; Nisco, Alessia De; Latronico, Tiziana; Leone, Piero; Petrosillo, Giuseppe; Liuzzi, Grazia Maria; Ryder, Bryony; Inbar‐Feigenberg, Michal; Colella, Matilde; Lezza, Angela Maria Serena; Olsen, Rikke K.J.; Barile, Maria

doi:10.1080/10715762.2022.2146501

Cited by 3 publications

(2 citation statements)

References 58 publications

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“…Total cellular RNA was extracted from cells by using the RNeasyÒ Mini Kit (Qiagen, Cat# 74104) and reverse-transcribed to cDNA by using the RevertAid First Strand cDNA Synthesis Kit (Thermo Fisher Scientific, Cat# K1621) following the instructions of the manufacturer's protocols, essentially as in [52]. PCR was performed using Wonder-Taq -Taq polymerase (Euroclone, Pero (MI), Italy, Cat# EME020001) according to the manufacturer's instructions using gene-specific primers (FLAD1 FW 5 0 -GCAGGTGCCCTACAGACCATT-3 0 REV 5 0 -GTCTTT GCCCCCGTTGAAG-3 0 ; SDHA FW 5 0 -GCATTAT AACATGGGCGGC-3 0 REV 5 0 -GCCTGCATGACTCTT CGATG-3 0 ; b-actin FW 5 0 -CTGGGAGTGGGT GGAGGC-3 0 REV 5 0 -TCAACTGGTCTCAAGTCAGTG -3 0 , LSD1 5 0 -TTCAGGAGTTGGAAGCGAAT-3 0 REV 5 0 -GAACCTGTCGCACTGCGTA-3 0 ).…”

Section: Semi-quantitative and Quantitative Rt-pcrmentioning

confidence: 99%

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

et al. 2023

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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 (IC50 = 1.2 μm) and PANC‐1‐derived CSCs' lysate (IC50 = 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.

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Section: Semi-quantitative and Quantitative Rt-pcrmentioning

confidence: 99%

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

et al. 2023

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“…The phenotype is extremely heterogeneous; some patients have a severe disorder with early onset, cardiac and respiratory failure resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Although there is no gold standard treatment, some patients show significant improvement with riboflavin treatment 6 , 7 . In this study, we report a FLAD1 mutations in a 5-year-old boy, which led to lipid storage myopathy due to FAD synthetase deficiency.…”

Section: Introductionmentioning

confidence: 99%

Detection of FLAD1 mutations and lipid storage myopathy in a 5-year-old boy: a case report study

Shojaie

Ghelichi-Ghojogh

2023

Annals of Medicine &Amp; Surgery

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Introduction and importance: Lipid storage myopathy due to flavin adenine dinucleotide synthetase 1 (FLAD1) deficiency is an autosomal recessive error of metabolism that causes variable mitochondrial dysfunction. Case presentation: At the age of 3, the patient was found to have movement problems, such as difficulty rising from a chair (Gower’s sign) and climbing stairs, which led to hospital admission and diagnosis. At the age of 4, carrier detection for spinal muscular atrophy was normal; however, at the age of 5, whole-exome sequencing revealed a pathogenic variant of Chr1: 154960762: A>T c.A554T:p.D185V in exon-2 of FLAD1 gene was identified as homozygous. Clinical discussion: In general, it is expected that the treatment of type 2 FLAD1 gene mutation with riboflavin has a better prognosis, but these interventions may not be sufficient for the survival of the patient. Treatment with riboflavin has increased various functions, including skeletal-muscular, and cardiovascular function. As a result, like the patient in our study, the mutation in exon-2 is more severe and less responsive to riboflavin treatment. Conclusion: Checking the FLAD1 gene is recommended in all people with multiple acyl-CoA dehydrogenase deficiency.

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Exploring the impact of flavin homeostasis on cancer cell metabolism

Nisco,

Tolomeo,

Scalise

et al. 2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2

Cited by 3 publications

References 58 publications

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

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

Detection of FLAD1 mutations and lipid storage myopathy in a 5-year-old boy: a case report study

Exploring the impact of flavin homeostasis on cancer cell metabolism

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