Abstract
An increasing number of studies have shown that the promising compound resveratrol treats multiple diseases, such as cancer and aging; however, the resveratrol mode-of-action (MoA) remains largely unknown. Here, by virtue of multiple omics approaches, we adopted fission yeast as a model system with the goal of dissecting the common MoA of the anti-proliferative activity of resveratrol. We found that the anti-proliferative activity of resveratrol is mainly due to its unique role of inhibiting the separation of sister cells, similar phenotype with the C2H2 zinc finger transcription factor Ace2 knock-out strain. Microarray analysis shown that resveratrol has extensive impact on the fission yeast transcription levels. Among the changed gene’s list, 40% of up-regulated genes are Core Environmental Stress Responses genes, and 57% of the down-regulated genes are periodically expressed. Moreover, resveratrol leverages the metabolome, which unbalances the intracellular pool sizes of several classes of amino acids, nucleosides, sugars and lipids, thus reflecting the remodulated metabolic networks. The complexity of the resveratrol MoA displayed in previous reports and our work demonstrates that multiple omics approaches must be applied together to obtain a complete picture of resveratrol’s anti-proliferative function.
Highlights
Resveratrol was first characterized in the white hellebore root in 1940 [1], this natural product has started to attract attention over the past 20 years primarily due to the discovery of its extensive pharmacological potential to treat and/or prevent diverse human diseases, such as cancer, metabolic disorders and aging-associated diseases [1,2,3]
After analyzing the down-regulated gene list, we found there is over 57% down-regulated genes (56 genes in total, p-value = 1.19E-35) are recognized as “Cell cycle periodically expressed” category (Table 2), clearly support the cell division defect phenotype we observed after resveratrol adding
Our studies elucidated that the transcription factor-mediated cell division inhibiting and global metabolic reprogramming are the major MoA of resveratrol in response to its anti-proliferative function in fission yeast
Summary
Resveratrol was first characterized in the white hellebore root in 1940 [1], this natural product has started to attract attention over the past 20 years primarily due to the discovery of its extensive pharmacological potential to treat and/or prevent diverse human diseases, such as cancer, metabolic disorders and aging-associated diseases [1,2,3]. Compared with the rapidly growing improvements in the animal model systems and clinical investigation, the understanding of the resveratrol’s mode-of-action (MoA), especially at the cellular and molecular levels, still remains incomplete. Resveratrol binds multiple intracellular molecular targets depending on the specific disease model [2]. In terms of its anti-cancer bioactivity, resveratrol arrests the cell cycle progression of diverse cancer cell lines, which is the consequence of resveratrol binding to the RAC-α serine/threonine protein kinase (AKT) and triggering the PI3K/AKT/FOXO pathway, which is responsible for regulating the critical cell cycle controller cyclin D1 [3]. CAMP activates the CamKKβ-AMPK pathway through phospholipase C, increases the abundance of NAD+, activates Sirtuin 1 (Sirt1), and eventually improves mitochondrial function. Resveratrol was proven to be a post-transcriptional regulator through its selective binding of the RNA-binding protein KSRP during pro-inflammatory procedures [5] and to the small RNAs miR-33a and miR-122 in hepatic cells [6]
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