β-glucan from Lentinus edodes inhibits breast cancer progression via the Nur77/HIF-1α axis

Abstract

Background: β-glucan from Lentinus edodes(LNT) is a plant-derived medicinal fungus possessing significant bioactivities on anti-tumor. Both hypoxia-induced factor-1α (HIF)-1α and Nur77 have been shown to be involved in the development of breast cancer. However, there is yet no proof of Nur77/HIF-1α involvement in the process of LNT-mediated tumor-inhibition effect. Methods: Immunohistochemistry, immunofluorescence and hematoxylin-eosin staining were used to investigate tumor growth and metastasis in MMTV-PyMT transgenic mice. Proliferation and metastasis-associated molecules were determined by western blotting andreverse transcription-quantitative PCR. Hypoxic cellular model was established under the exposure of CoCl2. Small interference RNA was transfected using Lipofectamine reagent. The ubiquitin proteasome pathway was blunted by adding the proteasome inhibitor MG132. Results: LNT inhibited the growth of breast tumors and the development of lung metastases from breast cancer, accompanied by a decreased expression of HIF-1α in the tumor tissues. In in vitroexperiments, hypoxia induced the expression of HIF-1α and Nur77 in breast cancer cells, while LNT addition down-regulated HIF-1α expression in an oxygen-free environment, and this process was in a manner of Nur77 dependent. Mechanistically, LNT-evoked the downregulation of HIF-1α involved the Nur77-mediated ubiquitin proteasome pathway. A strong positive correlation between Nur77 and HIF-1α expression in human breast cancer specimens was also confirmed. Conclusion: Therefore, LNT appears to inhibit the progression of breast cancer partly through the Nur77/HIF-1α signaling axis. The findings of the present study may provide a theoretical basis for targeting HIFs in the treatment of breast cancer.

β‐Glucan produced by Lentinus edodes suppresses breast cancer progression via the inhibition of macrophage M2 polarization by integrating autophagy and inflammatory signals

“…Qin et al reported that Nur77 promotes cigarette smoke‐induced autophagic cell death by increasing the dissociation of Bcl2 from beclin‐1 38 . Abnormal expression or function of Nur77 can also lead to various diseases, including breast cancer 27,39,40 . Previous studies have reported that p62 plays a role in inhibiting cell autophagy signals; affects proliferation, differentiation, and apoptotic events; is abnormally expressed as an oncogenic factor in several types of tumors; and inhibits the mTOR signaling pathway to coregulate tumorigenesis 41,42 .…”

“…The cells were seeded in 6-well or 24-well plates at a density of 10 5 cells/cm 2 a day before the experiments. Tumor necrosis factor-α (TNF-α) (20 ng/mL) and different concentrations of LNT (50,125,250,500, and 1000 μg/mL) were added to the cells at 70%-80% confluence, and the plates were incubated for 24 h. 27 Conditioned medium was prepared by culturing tumor cells in medium supplemented with β-glucans or phosphate buffer (PBS) for 24 h, and the supernatant was used as the medium for culturing the macrophages; after 24 h of incubation in the conditioned medium, the supernatant of the macrophage culture was used to treat T47D tumor cells.…”

Therapeutic potential of NR4A1 in cancer: Focus on metabolism

“…NR4A1 is a well-studied transcription factor, and recent researches focus on identifying its genomic and non-genomic effects in cancers, including melanoma ( 106 ), breast cancer ( 107 ), and colorectal cancer ( 31 ). As described above, NR4A1 exhibits important functions in cancer cell metabolic reprogramming.…”

Effects of Medicinal Fungi-Derived β-Glucan on Tumor Progression

“…Numerous molecular targets of mushroom-derived β-glucan involve NF-κB inhibitors, protein kinase inhibitors, modulators of G1/S and G2/M checkpoints, inhibitors of MAPK protein kinase signaling pathways, cyclooxygenase inhibitors, and DNA polymerase inhibitors (for review, see Zaidman, Yassin, Mahajna, and Wasser (2005) [ 93 ]). In cases of lentinan, recent observation suggested that the breast cancer progression inhibition is modulated via the Nur77/HIF-1α axis [ 115 ]. The authors speculate that HIFs might be a potential target in breast cancer treatment.…”

“…Some direct effects on lung cancer cells were also described for β-glucan from Antrodia cinnamomea, with the supposed mechanism being regulation of the TGFβ/AKT/GSK3β axis [ 126 ]. β-glucan from Lentinus edodes can in some cases inhibit proliferation of breast cancer cells when used simultaneously with hypoxic conditions [ 115 ]. The problem of all these studies, however, is the fact that none of them were ever independently repeated.…”