Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells

Abstract

High-risk neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Understanding the molecular mechanisms involved in tumor development and progression is strategic for the improvement of pharmacological therapies. Notch was recently proposed as a pharmacological target for the therapy of several cancers and is emerging as a new neuroblastoma-related molecular pathway. However, the precise role played by Notch in this cancer remains to be studied extensively. Here, we show that Notch activation by the Jagged1 ligand enhances the proliferation of neuroblastoma cells, and we propose the possible use of Notch-blocking γ-secretase inhibitors (GSIs) in neuroblastoma therapy. Two different GSIs, Compound E and DAPT, were tested alone or in combination with 13-cis retinoic acid (RA) on neuroblastoma cell lines. SH-SY5Y and IMR-32 cells were chosen as paradigms of lower and higher malignancy, respectively. Used alone, GSIs induced complete cell growth arrest, promoted neuronal differentiation, and significantly reduced cell motility. The combination of GSIs and 13-cis RA resulted in the enhanced growth inhibition, differentiation, and migration of neuroblastoma cells. In summary, our data suggest that a combination of GSIs with 13-cis RA offers a therapeutic advantage over a single agent, indicating a potential novel therapy for neuroblastoma.

A NOTCH3 Transcriptional Module Induces Cell Motility in Neuroblastoma

“…In agreement with an aggressive function of NOTCH signaling in neuroblastoma, high levels of NOTCH1 protein predicted a poor prognosis in neuroblastoma (28). Inhibition of g-secretase activity, required for NOTCH activation, attenuated neuroblastoma cell growth in vitro (29) and in vivo (28).…”

Cooperation of deregulated Notch signaling and Ras pathway in human hepatocarcinogenesis

“…Recently, there was increasing evidence that aberrant Notch signaling activation was required for the tumor proliferative activity, such as T-cell acute lymphoblastic leukemias (T-ALLs) (Weng et al 2003;Palomero et al 2007;Vilimas et al 2007;Masuda et al 2009;Koch and Radtke 2007;Roy et al 2007), HCC (Ning et al 2009;Gao et al 2010), non-small cell lung cancer (Donnem et al 2010), breast cancers (Gramantieri et al 2007), colon cancer ), Hodgkin and large-cell lymphomas (Jundt et al 2002). Furthermore, selective blocking of Notch1 with pharmacological approaches could inhibit cancer cells proliferation in T-ALLs (Giovannini et al 2009;Rao et al 2009;Wu et al 2010;Lewis et al 2007), HCC (Moellering et al 2009;Ning et al2009), as well as pancreatic cancer (Kimura et al 2007) and neuroblastoma (Ferrari-Toninelli et al 2010). However, further studies will be required to elucidate whether the molecular mechanisms underlying Notch activation in our experimental models operate in specific human tumors, and whether other Notch receptors and ligands had biological roles in our models.…”

The Different Faces of Angiogenesis in Neuroblastoma

“…Moreover, along with young age (<18 months) and localized disease, differentiation has been strongly correlated to a better prognosis (Ambros et al, 1996). Spontaneous or treatment-induced maturation characterizes a subgroup of neuroblastomas and constitutes the basis for maturation targeting therapies, such as retinoic acid treatment (Ferrari-Toninelli et al, 2010;Matthay et al, 1999;Mora et al, 2004;Giannini et al, 2000). Nevertheless, the molecular mechanisms that drive maturation of neuroblastic lesions are still poorly understood.…”

“…Nevertheless, the molecular mechanisms that drive maturation of neuroblastic lesions are still poorly understood. Schwannian stroma cells have been claimed to be implicated in differentiation of neuroblastomas (Coco et al, 2005;Ambros et al, 1996) as well as a large variety of transcriptional factors and different genes involved in neural development and differentiation of normal neuroectodermalderived tissues (Hoehner et al 1998;Kitlinska et al, 2005;Ferrari-Toninelli et al, 2010;Christiansen et al, 2000;Koppen et al, 2008). Gene expression profiles studies recently allowed to identify genes differentially expressed between undifferentiated and differentiated neuroblastic lesions.…”

“…Retinoic acid has been shown to induce neuroblastoma maturation throughout different molecular pathways (Ferrari-Toninelli, 2010). In patients after autologous stem cell transplantation retinoic acid has been introduced as a maintenance treatment (Matthay et al, 1999).…”