Retinoic acid-induced apoptosis of the CHP134 neuroblastoma cell line is associated with nuclear accumulation of p53 and is rescued by the GDNF/Ret signal

Abstract

The addition of ligands, glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN), inhibited apoptosis as well as nuclear accumulation of p53 in the cell. The present results suggest that the RA-induced apoptosis of NBL cells is associated with activation of both the caspase cascade and the p53-mediated pathway with its nuclear translocation. The neurotrophic signal through the GDNF-Ret system may prevent the neuronal cell death.

Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma

“…Consistent with this notion, p53 was predominantly expressed in the cytoplasm of neuroblastoma cells examined in this study (data not shown). We have previously shown that cytoplasmic p53 is translocated into the nucleus of CHP134 cells in response to ATRA (Takada et al, 2001); however, our present results suggest that translocated p53 was not functional. Indeed, it is reported that p53 in neuroblastoma cells is not functional even after its enforced translocation into the nucleus (Ostermeyer et al, 1996).…”

“…All-trans-retinoic acid activates phosphatidylinositol 3 0 -kinase-Akt pathway that plays an important role in neuronal differentiation (Encinas et al, 1999;Lopez-Carballo et al, 2002), and it reduces the expression levels of MYCN (Thiele et al, 1985) and upregulates the cyclin-dependent kinase (CDK) inhibitor p27 KIP1 in association with the ATRA-induced cell cycle arrest in neuroblastoma cells (Lee et al, 1996;Nakamura et al, 2003). In addition, certain neuroblastoma cells underwent apoptosis in response to ATRA (Piacentini et al, 1992;Takada et al, 2001;Nagai et al, 2004). Consistent with these observations, 13-cis-RA treatment after intensive chemotherapy improved an event-free survival rate of the patients with aggressive neuroblastomas with 17% increase (Villablanca et al, 1995;Matthay et al, 1999).…”

Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition

“…Recent studies have documented an increase in RET expression in response to retinoic acid treatment and have shown that RET inhibition interferes with retinoic acid-induced differentiation [46][47][48][49]. Other recent studies have demonstrated that retinoic acid-induced differentiation of neuroblastoma cells creates dependence on neurotrophin and glial-derived neurotrophic factor signaling, suggesting that retinoic acid treatment may sensitize neuroblastoma cells to inhibition of these pathways [50,51]. Prior studies have identified synergistic efficacy of 13-cisretinoic acid and the RET inhibitor vandetanib [27], suggesting that combined effects on RET may be responsible for the synergism seen with cabozantinib.…”

A novel therapeutic combination for neuroblastoma

“…Recent studies have documented that an increase in RET expression occurs in response to CRA treatment, that activated RET can stimulate neuroblastoma cell differentiation, and that RET inhibition interferes with differentiation induced by CRA 14, 32‐34. Other recent studies have demonstrated that CRA‐induced differentiation of neuroblastoma cells creates dependence on neurotrophin and glial‐derived neurotrophic factor signaling, suggesting that CRA treatment may sensitize neuroblastoma cells to inhibition of these pathways 6, 7…”

“…Retinoids, including CRA, have potent differentiating effects on neuroblastoma tumor cells. Retinoic acid treatment improves outcomes of children with neuroblastoma2 and increases expression levels of several receptor tyrosine kinases,6, 7 which may stimulate prosurvival pathways during differentiation. Induction of differentiation while targeting prosurvival pathways may have significant therapeutic benefit.…”