Subtype of Neuroblastoma Cells with High KIT Expression Are Dependent on KIT and Its Knockdown Induces Compensatory Activation of Pro-Survival Signaling.
Timofey LebedevAnton BuzdinElmira KhabushevaPavel V SpirinMaria SuntsovaMaxim I SorokinVladimir PopenkoPetr RubtsovVladimir PrassolovPublished in: International journal of molecular sciences (2022)
Neuroblastoma (NB) is a pediatric cancer with high clinical and molecular heterogeneity, and patients with high-risk tumors have limited treatment options. Receptor tyrosine kinase KIT has been identified as a potential marker of high-risk NB and a promising target for NB treatment. We investigated 19,145 tumor RNA expression and molecular pathway activation profiles for 20 cancer types and detected relatively high levels of KIT expression in NB. Increased KIT expression was associated with activation of cell survival pathways, downregulated apoptosis induction, and cell cycle checkpoint control pathways. KIT knockdown with shRNA encoded by lentiviral vectors in SH-SY5Y cells led to reduced cell proliferation and apoptosis induction up to 50%. Our data suggest that apoptosis induction was caused by mitotic catastrophe, and there was a 2-fold decrease in percentage of G2-M cell cycle phase after KIT knockdown. We found that KIT knockdown in NB cells leads to strong upregulation of other pro-survival growth factor signaling cascades such as EPO, NGF, IL-6, and IGF-1 pathways. NGF, IGF-1 and EPO were able to increase cell proliferation in KIT-depleted cells in an ERK1/2-dependent manner. Overall, we show that KIT is a promising therapeutic target in NB, although such therapy efficiency could be impeded by growth factor signaling activation.
Keyphrases
- cell cycle
- cell cycle arrest
- cell proliferation
- growth factor
- pi k akt
- induced apoptosis
- poor prognosis
- endoplasmic reticulum stress
- cell death
- signaling pathway
- tyrosine kinase
- oxidative stress
- binding protein
- papillary thyroid
- stem cells
- anti inflammatory
- squamous cell carcinoma
- long non coding rna
- single cell
- deep learning
- epidermal growth factor receptor
- young adults
- growth hormone