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Series GSE275316 Query DataSets for GSE275316
Status Public on Nov 28, 2024
Title SULFORAPHANE ACUTELY ACTIVATES MULTIPLE STARVATION RESPONSE PATHWAYS
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Sulforaphane (SFN) is an isothiocyanate present in cruciferous vegetables that ameliorates various disease models in rodents (e.g., cancer, diabetes, seizures) that are likewise mitigated by dietary restriction leading us to test the hypothesis that this compound elicits cellular responses consistent with being a fasting mimetic. Using untransformed human retinal pigment epithelial (RPE-1) cells, we report that SFN impacted multiple nutrient-sensing pathways consistent with a fasting state. SFN treatment (i) increased mitochondrial resistance to oxidative stress, (ii) acutely suppressed markers of mTORC1/2 activity via inhibition of insulin signaling, (iii) upregulated autophagy and further amplified autophagic flux induced by rapamycin or nutrient deprivation while concomitantly promoting lysosomal and mitochondrial biogenesis, (iv) acutely decreased glucose uptake and lactate secretion followed by an adaptive rebound that coincided with suppressed protein levels of thioredoxin-interacting protein (TXNIP) due to early transcriptional down-regulation. This early suppression of TXNIP mRNA expression could be overcome with exogenous glucosamine consistent with SFN inhibiting glutamine F6P amidotransferase (GFAT), the rate limiting enzyme of the hexosamine biosynthetic pathway. SFN also altered multiple glycolytic and tricarboxylic acid (TCA) cycle intermediates while reducing the inhibitory phosphorylation on pyruvate dehydrogenase, indicative of an adaptive cellular starvation response directing pyruvate into acetyl coenzyme A for uptake by the TCA cycle. RNA-seq of cells treated for 4hrs with SFN confirmed the activation of signature starvation-responsive transcriptional programs. Concomitant with stabilizing and activating the transcription factor NF-E2-related factor 2, we posit that the fasting-mimetic properties of SFN underlie both the therapeutic efficacy and potential toxicity of this phytochemical.
 
Overall design mRNA profiling of tissue culture cells (human telomerase-immortalized RPE-1 cells) that were treated with either sulforaphane or vehicle (DMSO) for 4 hours (N=5 replicates for each treatment)
 
Contributor(s) Plafker KS, Plafker SM, Georgescu C, Pranay A, Pezant N
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Submission date Aug 20, 2024
Last update date Nov 28, 2024
Contact name Jonathan Wren
E-mail(s) Jonathan-Wren@omrf.org
Phone (405) 271-6989
Organization name OMRF
Department Genes & Human Disease Research Program
Street address 825 N.E. 13th Street
City Oklahoma City
State/province OK
ZIP/Postal code 73104
Country USA
 
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (10)
GSM8474648 DMSO_1_S37
GSM8474649 DMSO_2_S38
GSM8474650 DMSO_3_S39
Relations
BioProject PRJNA1150243

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE275316_rawCounts.txt.gz 562.7 Kb (ftp)(http) TXT
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Raw data are available in SRA

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