Dual-Targeting AKT2 and ERK in cancer stem-like cells in neuroblastoma.

Dual-Targeting AKT2 and ERK in cancer stem-like cells in neuroblastoma. Oncotarget. 2019 Sep 24;10(54):5645-5659 Authors: Kim KW, Kim JY, Qiao J, Clark RA, Powers CM, Correa H, Chung DH Abstract 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 ser...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research