Polydatin down-regulates the phosphorylation level of STAT3 and induces pyroptosis in triple-negative breast cancer mice with a high-fat diet

Abstract

Background: To explore the impact of polydatin on mice with triple-negative breast cancer (TNBC) receiving a high-fat diet, as well as the underlying processes.Methods: A total of 40 female Balb/c mice were randomly separated into 4 groups (4T1+polydatin+fat diet group, 4T1+high-fat diet group, 4T1+polydatin group, and 4T1 group). To establish the obese TNBC mouse model, TNBC was xenografted 1×10 5 4T1 cells/50 μL per mouse at the right fourth mammary fat pad under anesthesia and the mice were fed a high fat diet. When the experiment was completed, total plasma cholesterol (TC) and cancer antigen (CA)15-3 were measured. The enzyme-linked immunosorbent assay (ELISA) method was used detect CA15-3. Oil red O staining was used to observe the morphological changes. Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR) were used to detect the corresponding protein expression and the messenger RNA (mRNA) level.Results: Polydatin decreased the degree of fatty liver, as determined by oil red O staining. The TC level in the 4T1+fat diet group was significantly higher, and it was decreased in the 4T1+polydatin group. The results of ELISA showed that compared with the 4T1 group, CA15-3 was significantly increased in the 4T1+fat diet group, and polydatin was shown to significantly reduce the expression of CA15-3. Polydatin inhibited p-JAK2 and p-STAT3 mRNA and protein levels. Polydatin increased pyroptosis-related gene mRNA and protein level. Conclusions:We believe that polydatin can effectively reduce blood lipid levels in TNBC mice with a high-fat diet, and play an anticancer role in TNBC. The underlying mechanism may be related to the JAK2/ STAT3 signaling pathway and pyroptosis in TNBC. Our results contribute to validating the traditional use of polydatin in the treatment of TNBC with hyperlipidemia.

Targeted Pyroptosis Is a Potential Therapeutic Strategy for Cancer

“…signaling pathway [169][170][171] 17β-estradiol Induces the activation of NLRP3 infammasome [173] Increases FOXO3 phosphorylation, induces oxidative stress, and downregulates IL-6/STAT3 signaling [174,175] Berberine Induces caspase-1-dependent pyroptosis [176] Regulates NF-κB/p65 pathway and induces adenosine AMPK-mediatedcaspase-dependent apoptosis [177,178] Euxanthone Promotes pyroptosis in a caspase-dependent manner [156] Alpinumisofavone Induces NLRP3 infammasome-mediated pyroptosis [157] Breast cancer Polydatin Downregulates the JAK2 and STAT3 levels [184] Suppresses the ROS/PI3K/Akt pathway [185] Cisplatin Activates the NLRP3/caspase-1/GSDMD pathway [186] Downregulates the PI3K/Akt/mTOR signaling pathway [187] Table 1: Continued.…”

“…It is confrmed that PRGs may serve as an important prognostic predictor and a chemotherapy target for the treatment of BC [179][180][181][182][183]. In addition, polydatin (PD) downregulates the janus kinase (JAK) 2 and STAT3 levels thus induces pyroptosis, which play an anticancer role in triple-negative BC (TNBC) [184]. Moreover, PD induces apoptosis by suppressing the ROS/ PI3K/Akt pathway to inhibit cell proliferation, migration, and invasion of BC cells [185].…”

Exploring Intervention of Selenium on Gut Microbiota Homeostasis and Corresponding Genetic Metabolism in Mice with Breast Cancer on a High-fat Diet Using Metagenomics Sequencing

“…Similar to the conclusion of Xuepeng Chi et al (Chi et al, 2022), the relative abundance of Lachnospiraceae and Prevotellaceae increased and the abundance of Helicobacterceae decreased after increasing the content of selenium in the ingested food, and the correlation analysis suggested that selenium could optimize the functional network of gut microbiota and optimize the interaction of gut microbiota and host. It has been reported that Faecalibacterium prausnitzii supernatant can inhibit the growth of breast cancer cells by inhibiting the IL-6/STAT3 pathway (Ma et al, 2020), suggesting that this class of bacteria may contribute to breast cancer prevention, and that reduction of this class of bacteria may promote breast cancer progression, and our previous study found that decreasing STAT3 phosphorylation can effectively induce apoptosis and pyroptosis in breast cancer cells exposed to high-fat conditions (Liu et al, 2022b). There was a trend toward enrichment in several KEGG pathways related to RNA anabolism in the selenium intervention group, although not signi cant, and notably, there was a trend toward decreased Fatty-acid-biosynthesis related to fatty acid anabolism, perhaps suggesting a possible role for selenium in the biosynthesis of fatty acids in breast cancer bearing mice fed a high-fat diet, selenium can inhibit fat accumulation and has anti-in ammatory activity which has been con rmed by the study of Liu et al (Liu et al, 2022a).…”

Pyroptosis and inflammasomes in cancer and inflammation

“…Metformin treatment greatly decreased breast cancer cell, colon cancer cell, and liver cancer cell viability and induced pyroptosis by improving the AMPK/SIRT1 pathway, upregulating NF‐κB p65 expression, and cleaving GSDME with caspase 3, 131 Docosahexaenoic acid (DHA) may trigger pyroptosis by boosting NF‐κB nuclear translocation, caspase 1, and GSDMD activation, 132 as well as activating the AIM2/caspase 3/DFNA5 pathway, 133 Nobiletin (NOB), a retinoid acid receptor‐related orphan receptors (RORs) agonist, 134 induces the pyroptosis of breast cancer cells via the miR‐200b/JAZF1/NF‐κB axis to stop tumorigenesis 135 . Polydatin, a monocrystalline compound isolated from Polygonum cuspidatum Sieb, 136 blocks the JAK2/STAT3 pathway and raises the expression of NLRP3, caspase 1, IL‐1β, and IL‐18 to contribute to the activation of pyroptosis in triple‐negative breast cancer 137 . Tetraarsenic hexoxide (As4O6) could increase mitochondrial ROS generation by preventing STAT3 phosphorylation, causing caspase 3/GSDME‐dependent pyroptotic cell death and ultimately inhibiting tumor proliferation and metastasis in triple‐negative breast cancer cells 138 .…”