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ORIGINAL RESEARCH article

Front. Nutr.
Sec. Nutrition and Metabolism
Volume 11 - 2024 | doi: 10.3389/fnut.2024.1485466
This article is part of the Research Topic Sulforaphane and Isothiocyanates in Health View all 8 articles

SULFORAPHANE ACUTELY ACTIVATES MULTIPLE STARVATION RESPONSE PATHWAYS

Provisionally accepted
Kendra S Plafker Kendra S Plafker 1Constantin Georgescu Constantin Georgescu 2Nathan Pezant Nathan Pezant 3Atul Pranay Atul Pranay 1Scott Plafker Scott Plafker 1*
  • 1 Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States
  • 2 Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, United States
  • 3 Center for Biomedical Data Sciences, Oklahoma Medical Research Foundation, Oklahoma City, United States

The final, formatted version of the article will be published soon.

    Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables that has demonstrated anti-cancer, anti-microbial and anti-oxidant properties. SFN ameliorates various disease models in rodents (e.g., cancer, diabetes, seizures) that are likewise mitigated by dietary restrictions leading us to test the hypothesis that this compound elicits cellular responses consistent with being a fasting/caloric restriction mimetic. Using immortalized human retinal pigment epithelial cells, we report that SFN impacted multiple nutrient-sensing pathways consistent with a fasted state. SFN treatment (i) increased mitochondrial mass and 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 biogenesis, and (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, the rate limiting enzyme of the hexosamine biosynthetic pathway. SFN also altered levels of 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 4h with SFN confirmed the activation of signature starvation-responsive transcriptional programs. Collectively, these data support that the fasting-mimetic properties of SFN could underlie both the therapeutic efficacy and potential toxicity of this phytochemical.

    Keywords: Sulforaphane, Starvation, Autophagy, mTOR, Txnip, Sestrin 2

    Received: 23 Aug 2024; Accepted: 11 Dec 2024.

    Copyright: © 2024 Plafker, Georgescu, Pezant, Pranay and Plafker. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Scott Plafker, Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.