Elevated expression of LGR5 and WNT signalling factors in neuroblastoma cells with acquired drug resistance

Abstract

word count 207 Word count 3,917 Figures 6 2 Abstract Neuroblastoma (NB) is the most common paediatric solid cancer with high fatality, relapses and acquired resistance to drug therapy. The clinical challenge NB poses requires new therapeutic approaches to improve survival rates.The WNT signalling pathway is crucial in embryonic development but has also been reported to be dysregulated in glioblastoma, ovarian, breast and colorectal cancer.LGR5 is a receptor which potentiates the WNT/β-catenin signalling pathway, hence contributing to cancer stem cell proliferation and self-renewal.LGR5 has been reported to promote both development and survival of colorectal cancer and glioblastomas.Our previous study illustrated that LGR5 is associated with aggressiveness in NB cell lines established at different stages of treatment. Following these findings, we investigated whetherLGR5 is involved in acquired drug resistance via the WNT pathway in NB cell lines.Cell lines in this study have an acquired drug resistance to vincristine (VCR) or doxorubicin (DOX).In this study, we showed LGR5-LRP6 cooperation with enhanced expression of both proteins in SHSY5YrVCR, IMR32rDOX, IMR5rVCR and IMR5rDOX NB cell lines compared to paired parental cells. We also found elevated expression of β-catenin in cell lines with acquired drug resistance is indicative of β-catenin-dependent WNT signalling.This study warrants further investigation into the role of the WNT signalling pathway in acquired drug resistance.

Neural crest cells development and neuroblastoma progression: Role of Wnt signaling

“…Similar increased sensitivity and decreased β‐catenin expression were observed in human SH‐SY5Y and IMR32 cells towards DOX after XAV939 treatment (Suebsoonthron et al, 2017). Another study reported that overexpression of LGR5 and Wnt signaling imparted resistance in SH‐SY5Y, IMR‐32 and IMR‐5 cell lines against vincristine (VCR) or DOX (Myssina et al, 2018). The expressions of FZD6, a Wnt receptor, is inversely proportional to the overall survival of NB patients, which developed tumorospheres and aggressive tumors more readily (Aravindan et al, 2019).…”