The inhibition of GHR enhanced cytotoxic effects of etoposide on neuroblastoma

Abstract

Etoposide, a DNA damage-inducing agent, is widely used to treat neuroblastoma. Etoposide binds to and inhibits topoisomerase II, thereby inducing the DNA damage response. However, the underlying mechanism of etoposide resistance in neuroblastoma remains unclear. The results of the present study revealed that etoposide upregulated growth hormone receptor (GHR) expression levels in etoposide-resistant neuroblastoma cells, suggesting that GHR upregulation may be involved in the underlying mechanism of etoposide resistance. Thus, the combined effect of GHR knockdown and etoposide treatment on cell viability, apoptosis and migration in vitro, as well as tumor growth in mouse xenograft models in vivo, was subsequently analyzed. The results of cell viability and colony formation assays demonstrated that GHR knockdown enhanced the inhibitory effects of etoposide on cell viability and sensitized cells to etoposide. The enhanced cell viability was discovered to be, at least in part, due to the increase in etoposide-induced apoptosis following GHR knockdown. Moreover, the knockdown of GHR enhanced the inhibitory effect of etoposide on cell migration. Mouse xenograft studies confirmed the effects of GHR silencing in etoposide-resistant neuroblastoma progression in vivo. Furthermore, the effects of GHR knockdown in etoposide resistance were hypothesized to occur via the inactivation of the MEK/ERK signaling pathway. In conclusion, the results of the present study provided novel insight into the underlying mechanism of etoposide resistance and a potential target for the treatment of etoposide-resistant neuroblastoma.