Id-1 Is a Key Transcriptional Regulator of Glioblastoma Aggressiveness and a Novel Therapeutic Target

Abstract

Glioblastoma (GBM) is the most common form of primary adult brain tumors. A majority of GBMs grow invasively into distant brain tissue, leading to tumor recurrence, which is ultimately incurable. It is, therefore, essential to discover master regulators that control GBM invasiveness and target them therapeutically. We demonstrate here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of GBM cell lines and primary GBM cells. Id-1 expression levels positively correlate with glioma cell invasiveness in culture and with histopathological grades in patient biopsies. Id-1 knockdown dramatically reduces GBM cell invasion that is accompanied by profound morphological changes and robust reduction in expression levels of “mesenchymal” markers, as well as inhibition of self-renewal potential and down-regulation of glioma stem cell markers. Importantly, genetic knockdown of Id-1 leads to a significant increase in survival in an orthotopic model of human GBM. Furthermore, we show that a non-toxic compound, cannabidiol, significantly down-regulates Id-1 gene expression and associated glioma cell invasiveness and self-renewal. Additionally, cannabidiol significantly inhibits the invasion of GBM cells through an organotypic brain slice and glioma progression in vivo. Our results suggest that Id-1 regulates multiple tumor-promoting pathways in GBM, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of GBM patients.

Curcumin Inhibits Expression of Inhibitor of DNA Binding 1 in PC3 Cells and Xenografts

“…In previous study, we found that down regulation of Id1 by small interfere RNA in PC3 cells can decrease cell viability, induce cell apoptosis and senescence (Yu et al, 2011). The similar effects of targeting Id1 mRNA was also found in other kinds of cancer cells (Dong et al, 2011;Soroceanu et al, 2013). So inactivation of Id1 may become a potential intervention in some human cancers.…”

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

“…The biological roles and mechanisms of ID family proteins in glioblastoma have been the subject of intense recent investigation (23,(33)(34)(35)(36). Benezra and colleagues (23) identified a self-renewing subpopulation expressing high levels of Id1 in a PDGFB-driven Arf −/− mouse model of glioblastoma.…”

“…More recently, combined genetic deletion of Id1, Id2, and Id3 in a HrasV12 and p53 knockdown-driven mouse model of high-grade glioma inhibited in vivo tumorigenicity and caused GSC exit from the perivascular niche, suggesting functional redundancy among Id family members (35). However, acute knockdown of ID1 alone in human GSCs was sufficient to reduce tumor formation in vivo, suggesting compensatory mechanisms for acute ID1 loss may be less robust (36).…”

Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture

“…It is important to emphasize that the lipophilic nature of CBD triggers biologic responses that are independent of protein-mediated mechanisms, including rapid changes in both membrane lipid raft and cholesterol metabolism when applied at 5-20 mM (Ligresti et al, 2006;Rimmerman et al, 2011Rimmerman et al, , 2013. Additional examples of the protein-independent mechanism of CBD include increases in oxidative stress resulting in apoptosis, DNA damage, and autophagy in breast cancer cells (Shrivastava et al, 2011) and in glioma cells (Bisogno et al, 2001;Massi et al, 2004;Solinas et al, 2013;Soroceanu et al, 2013) when this compound is applied at 5-40 mM. Thus, there is a wide range of protein-dependent and protein-independent biologic activities induced by CBD applied in the micromolar range.…”

“…It has been shown that cannabidiol (CBD) exhibits antineoplastic activity in multiple GBM cell lines in culture and in xenograft mouse models (Massi et al, 2004(Massi et al, , 2006(Massi et al, , 2008Vaccani et al, 2005;Marcu et al, 2010;Torres et al, 2011;Nabissi et al, 2013;Solinas et al, 2013;Soroceanu et al, 2013). This antineoplastic activity is mediated through plasma membrane-associated receptors, including G protein-coupled receptor (GPR) 55 and transient receptor potential cation channel subfamily V member (TRPV) 1/2, and involves the production of reactive oxygen as well as induction of autophagy and apoptosis (Bisogno et al, 2001;Ligresti et al, 2006;Massi et al, 2006;Ford et al, 2010;Ramer et al, 2010;Yamada et al, 2010;Piñeiro et al, 2011;Anavi-Goffer et al, 2012).…”