zerumbone and Brain-Neoplasms

The most widespread and challenging aggressive malignant tumor in the brain is glioblastoma multiforme (GBM). GBM is characterized, in particular, by significant intratumor cell variability, high growth rates, and widespread invasiveness within the surrounding normal brain parenchyma. The present study aimed to examine the impact of the natural product Zerumbone, a promising sesquiterpenoid phytochemical from Zingiber zerumbet, on U-87 MG GBM cells and its underlying molecular mechanisms. At sub-lethal doses, Zerumbone exerted a concentration- and time-dependent suppression of cell migration ability utilizing scratch wound closure assay; it also inhibited GBM cells' invasion using Transwell invasion assay in a concentration-dependent fashion. The enzymatic activity of matrix metalloproteinase (MMP)-2/-9 and their protein expression has also been reduced by administration of Zerumbone. Furthermore, Zerumbone was revealed to downregulate the mRNA expression level of IL-1β and MCP-1, two genes contributing to MMPs expression. We also found that Zerumbone exerted an inhibitory effect on the expression of Akt and total p44/42 MAPK (Erk1/Erk2) against U-87 MG cells. These findings collectively provide further proof for the possible molecular signaling basis of the antimetastatic effects of Zerumbone as a promising phytochemical, indicating a therapeutic strategy for the treatment of GBM through repression of migration, invasion, and metastasis.

Topics: Brain Neoplasms; Cell Proliferation; Cell Survival; Glioblastoma; Humans; Neoplasm Invasiveness; Sesquiterpenes; Signal Transduction; Zingiber officinale

WW domain containing oxidoreductase, designated WWOX, FOR or WOX1, is a known pro-apoptotic factor when ectopically expressed in various types of cancer cells, including glioblastoma multiforme (GBM). The activation of sonic hedgehog (Shh) signaling, especially paracrine Shh secretion in response to radiation, is associated with impairing the effective irradiation of cancer cells. Here, we examined the role of Shh signaling and WOX1 overexpression in the radiosensitivity of human GBM cells. Our results showed that ionizing irradiation (IR) increased the cytoplasmic Shh and nuclear Gli-1 content in GBM U373MG and U87MG cells. GBM cells with exogenous Shh treatment exhibited similar results. Pretreatment with Shh peptides protected U373MG and U87MG cells against IR in a dose-dependent manner. Cyclopamine, a Hedgehog/Smoothened (SMO) inhibitor, reversed the protective effect of Shh in U87MG cells. Cyclopamine increased Shh plus IR-induced H2AX, a marker of DNA double-strand breaks, in these cells. To verify the role of Shh signaling in the radiosensitivity of GBM cells, we tested the effect of the Gli family zinc finger 1 (Gli-1) inhibitor zerumbone and found that it could sensitize GBM cells to IR. We next examined the role of WOX1 in radiosensitivity. Overexpression of WOX1 enhanced the radiosensitivity of U87MG (possessing wild type p53 or WTp53) but not U373MG (harboring mutant p53 or MTp53) cells. Pretreatment with Shh peptides protected both WOX1-overexpressed U373MG and U87MG cells against IR and increased the cytoplasmic Shh and nuclear Gli-1 content. Zerumbone enhanced the radiosensitivity of WOX1-overexpressed U373MG and U87MG cells. In conclusion, overexpression of WOX1 preferentially sensitized human GBM cells possessing wild type p53 to radiation therapy. Blocking of Shh signaling may enhance radiosensitivity independently of the expression of p53 and WOX1. The crosstalk between Shh signaling and WOX1 expression in human glioblastoma warrants further investigation.

Topics: Brain; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Glioblastoma; Hedgehog Proteins; Histones; Humans; Oxidoreductases; Radiation Tolerance; Radiation, Ionizing; Sesquiterpenes; Signal Transduction; Transcription Factors; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation; Veratrum Alkaloids; WW Domain-Containing Oxidoreductase; Zinc Finger Protein GLI1