Honokiol Eliminates Glioma/Glioblastoma Stem Cell-Like Cells Via JAK-STAT3 Signaling and Inhibits Tumor Progression by Targeting Epidermal Growth Factor Receptor

Abstract

Malignant gliomas are the most aggressive forms of brain tumors; whose metastasis and recurrence contribute to high rates of morbidity and mortality. Glioma stem cell-like cells are a subpopulation of tumor-initiating cells responsible for glioma tumorigenesis, metastasis, recurrence and resistance to therapy. Epidermal growth factor receptor (EGFR) has been reported to be dysregulated in most cancers, including gliomas and its functions are closely linked to initiating tumor metastasis and a very poor prognosis. In search for compounds that may reduce the tumorigenic potential of gliomas/glioblastomas honokiol attracted our attention. Honokiol, purified from the bark of traditional Chinese herbal medicine Magnolia species, is beneficial in vitro and in animal models via a variety of pharmacological effects, including anti-inflammatory, anti-angiogenetic, anti-arrhythmic and antioxidant activities, as well as anti-proliferative and proapoptotic effects in a wide range of human cancer cells. However, its effects on glioma cells are unknown. Here, we used different concentrations of honokiol in treating U251 and U-87 MG human glioma/glioblastoma cells in cell culture. Results showed that honokiol inhibited glioma cell viability and colony formation and promoted apoptosis. It also inhibited glioma cell migration/proliferation and invasion. In addition, honokiol promoted apoptosis and reduced Bcl-2 expression, accompanied by increase in Bax expression. Honokiol reduced expression of EGFR, CD133 and Nestin. Moreover, honokiol inhibited the activation of both AKT and ERK signaling pathways, increased active caspase-3 level and reduced phosphorylation of STAT3. U-87 MG xenografts in nude mice and in immunotolerant zebrafish yolk sac showed that honokiol inhibits tumor growth and metastasis. Altogether, results indicate that honokiol reduces tumorigenic potentials, suggesting hopes for honokiol to be useful in the clinical management of glioma/glioblastoma.

Honokiol: A Review of Its Anticancer Potential and Mechanisms

“…It was known that juvenile zebrafish (Danio rerio) or zebrafish embryos have the competency to study cancer cell invasion, metastasis, tumour-induced angiogenesis. Honokiol reduced U-87 MG human glioma/glioblastoma cell proliferation and migration in zebrafish yolk sac and in vivo xenograft nude mouse model [63]. These observations are associated with a reduction in EGFR, phosphorylated STAT3, CD133 and Nestin levels, thus highlighting the regulation of honokiol in EGFR-mediated STAT3/JAK signalling pathway to induce anti-tumour and anti-metastasis.…”

“…Honokiol has been shown to inhibit the invasion of HT-1080 human fibrosarcoma cells and U937 leukemic cells by inhibiting MMP-9 [160]. In addition, honokiol also reduced the protein levels of MMP2 and MMP9 in U251 human glioma and U-87 MG human glioblastoma cell lines in a dose-dependent manner [63]. The expression of MMP-2 and MMP-9 were also found to be decreased in both honokiol-treated A549 and H1299 cells (NSCLC cell lines), consistent with the decreased nuclear accumulation of β-catenin as both MMP-2 and MMP-9 are the downstream targets of β-catenin [44,161,162].…”

“…Chen et al [14] found that JJ012 human chondrosarcoma cells lose their mitochondrial membrane potential when treated at 10 µM of honokiol, thus leading to apoptosis. Other studies have also shown that honokiol markedly disrupted the balance of Bax/Bcl-2 ratio [13,18,34,63,[94][95][96][97]. The increasing ratio of proapoptotic to antiapoptotic Bcl-2 family proteins (Bax/Bcl-2) will induce the release of cytochrome c and other apoptogenic proteins through the mitochondrial membrane to the cytosol, subsequently leading to the activation of caspase cascade and apoptosis [34].…”

“…Therefore, one of the important steps in cancer management is to control tumour cell metastasis, especially for early-stage cancer patients [153]. Various studies have reported that honokiol has the capability to suppress tumour metastasis in different types of cancer including breast cancer [40,148,154], non-small cell lung cancer [44,155] ovarian carcinoma cells [28], lung cancer [50], U251 human glioma, as well as U-87MG and T98G human glioblastoma cell [63,65,94], oral squamous cell carcinoma (OSCC) [26], bladder cancer cell [143], pancreatic cancer [58], renal cell carcinoma [156,157], and gastric cancer cells [113]. For instance, the percentage of invading urinary bladder cancer (UBC) cells was significantly reduced by 67% and 92% upon 2.4 µg/mL and 4.8 µg/mL of honokiol treatment, respectively [143].…”

“…Furthermore, honokiol also demonstrated an inhibitory effect on the expression of matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9 proteins, which play an essential role in the metastatic process of tumour cells, as well as the regulation of angiogenesis in the maintenance of tumour cell survivability [44,63,143]. MMPs are a group of extracellular matrix degrading enzymes that control various normal cellular processes, such as cell growth, differentiation, apoptosis, and migration [153].…”