An immune-stimulating proteoglycan from the medicinal mushroom Huaier up-regulates NF-κB and MAPK signaling via Toll-like receptor 4

Abstract

Edited by Xiao-Fan WangTrametes robiniophila Murr. (Huaier) is a mushroom with a long history of use as a medicinal ingredient in China and exhibits good clinical efficacy in cancer management. However, the antitumor components of Huaier and the underlying molecular mechanisms remain poorly understood. Here, we isolated a proteoglycan with a molecular mass of ϳ5.59 ؋ 10 4 Da from Huaier aqueous extract. We named this proteoglycan TPG-1, and using FTIR and additional biochemical analyses, we determined that its total carbohydrate and protein compositions are 43.9 and 41.2%, respectively. Using biochemical assays and immunoblotting, we found that exposing murine RAW264.7 macrophages to TPG-1 promotes the production of nitric oxide (NO), tumor necrosis factor ␣ (TNF␣), and interleukin-6 (IL-6) through Toll-like receptor 4 (TLR4)-dependent activation of NF-B and mitogen-activated protein kinase (MAPK) signaling. Of note, the TPG-1 treatment significantly inhibited the tumorigenesis of human hepatoma HepG2 cells likely at least in part by increasing serum levels of TNF␣ and promoting leukocyte infiltration into tumors in nude mice. TPG-1 also exhibited good antitumor activity in hepatoma H22-bearing mice and had no obvious adverse effects in these mice. We conclude that TPG-1 exerts antitumor activity partially through an immune-potentiating effect due to activation of the TLR4 -NF-B/MAPK signaling cassette. Therefore, TPG-1 may be a promising candidate drug for cancer immunotherapy. This study has identified the TPG-1 proteoglycan as an antitumor agent and provided insights into TPG-1's molecular mechanism, suggesting a potential utility for applying this agent in cancer therapy.

RETRACTED: Huaier extract suppresses non‐small cell lung cancer progression through activating NLRP3‐dependent pyroptosis

“…that has been approved by the Chinese Food and Drug Administration for cololitis (Chen, Wu, et al, 2018a; Sun et al, 2017). The main active ingredient of huaier is polysaccharide, which is a binding protein composed of 18 monosaccharides combined with 18 kinds of amino acids (Luo et al, 2016; Yang, Fan, et al, 2019a). Increasing evidence confirmed that huaier could induce the differentiation and apoptosis of cancer cells, improve the killing ability of immune cells, reverse tumor‐associated drug resistance, and inhibit the migration and invasion of tumor cells, and so on (Bao et al, 2016; Li et al, 2015; Zheng et al, 2014).…”

Icariin‐induced inhibition of SIRT6/NF‐κB triggers redox mediated apoptosis and enhances anti‐tumor immunity in triple‐negative breast cancer

“…T reg cells specifically require c‐Rel to inhibit anti‐tumor effector responses. Yang et al revealed that Toll‐like receptor 4 (TLR4), which plays a vital role in innate immune response and cytokine production, closely participates in NF‐κB‐mediated immune regulation 62 . In our study, we found that icariin could significantly ameliorate the tumor immunosuppressive microenvironment by downregulating expression levels of PD‐L1, enhancing the proportion of infiltrating CD4 + /CD8 + T cells and reducing the abundance of MDSCs in tumors.…”

Huaier Suppresses Breast Cancer Progression via linc00339/miR-4656/CSNK2B Signaling Pathway

“…Polysaccharide was identified as a possible key ingredient in Huaier (2–4). Previous studies showed that Huaier exerted therapeutic effects on psoriasis (5), inflammation (6), and tuberous sclerosis (7). In dextran sulfate sodium-induced experimental colitis, Huaier suppressed the secretion of interleukin 1β (IL-1β) and the activation of caspase-1 via inhibiting NLRP3 inflammasome (8).…”