Emodin Suppresses Maintenance of Stemness by Augmenting Proteosomal Degradation of Epidermal Growth Factor Receptor/Epidermal Growth Factor Receptor Variant III in Glioma Stem Cells

Abstract

There is a growing body of evidence that small subpopulations of cells with stem cell-like characteristics within most solid tumors are responsible for the malignancy of aggressive cancer cells and that targeting these cells might be a good therapeutic strategy to reduce the risk of tumor relapse after therapy. Here, we examined the effects of emodin (1,3,8-trihydroxy-6-methylanthraquinone), an active component of the root and rhizome of Rheum palmatum that has several biological activities, including antitumor effects, on primary cultured glioma stem cells (GSCs). Emodin inhibited the self-renewal activity of GSCs in vitro as evidenced by neurosphere formation, limiting dilution, and soft agar clonogenic assays. Emodin inhibited the maintenance of stemness by suppressing the expression of Notch intracellular domain, nonphosphorylated b-catenin, and phosphorylated STAT3 proteins. In addition, treatment with emodin partially induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing radiation. Intriguingly, emodin induced proteosomal degradation of epidermal growth factor receptor (EGFR)/EGFR variant III (EGFRvIII) by interfering with the association of EGFR/ EGFRvIII with heat shock protein 90, resulting in the suppression of stemness pathways. Based on these data, we propose that emodin could be considered as a potent therapeutic adjuvant that targets GSCs.

Inhibitory effect of emodin on fatty acid synthase, colon cancer proliferation and apoptosis

“…Tomek et al (9) reported that inhibiting FASN with C75 results in the accumulation of ubiquitinated proteins, including PI3K and MAPK signaling proteins, in ovarian cancer (9). Emodin also induces the proteosomal degradation of EGFR/EGFR variant III in glioma stem cells (41). However, no previous study has reported that emodin induces the degradation of FASN protein.…”

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…Additionally, HSP90 promotes multicell spheroid formation, migration, and invasion of thyroid CSCs, and those CSC phenotype-related activities were sensitive to HSP90 inhibitors [74]. It was demonstrated on cultured glioma SCs that the association of HSP90 with EGFR/EGFRvIII preserves the receptor complexes from proteasomal degradation, thus supporting the work of cancer stemness-promoting pathways [75]. Under conditions of hypoxia and acidosis in the microenvironment of gliomas, tumorous (intracellular) HSP90 was upregulated in the hypoxic niches, which was correlated with both the CSC phenotype's expression and HSP90-dependent HIF upregulation [76].…”

Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics

“…Emodin effectively blocked the self‐renewal activity of glioma stem cells by suppressing crucial stemness signalling pathways involving Notch‐1, b‐catenin and STAT3. Emodin induced proteosomal degradation of EGFR/EGFRvIII by interfering with its association with Hsp90, leading to partial induction of apoptosis and sensitization of glioma stem cells to ionizing radiation (Kim et al ., ). Wang et al reported that emodin inhibited human cervical cancer HeLa cell proliferation by inducing apoptosis through the intrinsic mitochondrial and extrinsic death receptor pathways (Wang et al ., ).…”