RESUMEN
Obesity has a significant impact on endocrine function, which leads to metabolic diseases including diabetes, insulin resistance, and other complications associated with obesity. Development of effective and safe anti-obesity drugs is imperative and necessary. Equisetin (EQST), a tetramate-containing marine fungal product, was reported to inhibit bacterial fatty acid synthesis and affect mitochondrial metabolism. It is tempting to speculate that EQST might have anti-obesity effects. This study was designed to explore anti-obesity effects and underlying mechanism of EQST on 3T3-L1 adipocytes differentiated from 3T3-L1 cells. Oil Red O staining showed that EQST reduced lipid accumulation in 3T3-L1 adipocytes. Quantitative real-time polymerase chain reaction and Western blot analysis revealed that EQST significantly inhibited expression of adipogenesis/lipogenesis-related genes C/ebp-α, Ppar-γ, Srebp1c, Fas, and reduced protein levels. There was also increased expression of key genes and protein levels involved in lipolysis (Perilipin, Atgl, Hsl), brown adipocyte differentiation (Prdm16, Ucp1), mitochondrial biogenesis (Pgc1α, Tfam) and ß-oxidation Acsl1, Cpt1. Moreover, mitochondrial content, their membrane potential ΔΨM, and respiratory chain genes Mt-Co1, Cox7a1, Cox8b, and Cox4 (and protein) exhibited marked increase in expression upon EQST treatment, along with increased protein levels. Importantly, EQST induced expression and activation of AMPK, which was compromised by the AMPK inhibitor dorsomorphin, leading to rescue of EQST-downregulated Fas expression and a reduction of the EQST-increased expression of Pgc1α, Ucp1, and Cox4. Together, EQST robustly promotes fat clearance through the AMPK pathway, these results supporting EQST as a strong candidate for the development into an anti-obesity therapeutic agent.
RESUMEN
Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion: In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.
