Neuroblastoma remains one of the most difficult pediatric solid tumors to treat. In particular, the refractory and relapsing neuroblastomas are highly heterogeneous with diverse molecular profiles. We previously demonstrated that AKT2 plays critical roles in the regulation of neuroblastoma tumorigenesis. Here we hypothesize that targeting AKT2 could block the signal transduction pathways enhanced in chemo- and/or radiation-resistant neuroblastoma cancer stem-like cells. We found cell proliferation and survival signaling pathways AKT2/mTOR and MAPK were enhanced in cisplatin (CDDP)- and radiation-resistant neuroblastoma cells. Blocking these two pathways with specific inhibitors, CCT128930 (AKT2 inhibitor) and PD98059 (MEK inhibitor) decreased cell proliferation, angiogenesis, and cell migration in these resistant cells. We further demonstrated that the resistant cells had a higher sphere-forming capacity with increased expression of stem cell markers CD133, SOX2, ALDH, Nestin, Oct4, and Nanog. Importantly, the tumorsphere formation, which is a surrogate assay for self-renewal, was sensitive to the inhibitors of AKT2 and MAPK. Taken together, our findings suggest that CDDP- and radiation-resistant cancer stem-like neuroblastoma cells might serve as a useful tool to improve the understanding of molecular mechanisms of therapeutic resistance. This may aid in the development of more effective novel treatment strategies and better clinical outcomes in patients with neuroblastoma.
Keywords: AKT2; MAPK; chemotherapy; radiotherapy; resistance.
Copyright: © 2019 Kim et al.
Conflict of interest statement
CONFLICTS OF INTEREST The authors have no financial disclosures.
Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma.J Biol Chem. 2012 Sep 21;287(39):32800-24. doi: 10.1074/jbc.M111.308528. Epub 2012 Jul 30. J Biol Chem. 2012. PMID: 22847005 Free PMC article.
Key role of MEK/ERK pathway in sustaining tumorigenicity and in vitro radioresistance of embryonal rhabdomyosarcoma stem-like cell population.Mol Cancer. 2016 Feb 20;15:16. doi: 10.1186/s12943-016-0501-y. Mol Cancer. 2016. PMID: 26897742 Free PMC article.
Markedly increased Oct4 and Nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma.J Oral Pathol Med. 2011 Sep;40(8):621-8. doi: 10.1111/j.1600-0714.2011.01015.x. Epub 2011 Feb 22. J Oral Pathol Med. 2011. PMID: 21342274
Resistance to Cell Death and Its Modulation in Cancer Stem Cells.Crit Rev Oncog. 2016;21(3-4):203-219. doi: 10.1615/CritRevOncog.2016016976. Crit Rev Oncog. 2016. PMID: 27915972 Free PMC article. Review.
C-Met pathway promotes self-renewal and tumorigenecity of head and neck squamous cell carcinoma stem-like cell.Oral Oncol. 2014 Jul;50(7):633-9. doi: 10.1016/j.oraloncology.2014.04.004. Epub 2014 May 15. Oral Oncol. 2014. PMID: 24835851 Review.
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