Open Access

ARTICLE

Nutlin-3-Induced Sensitization of Non-Small Cell Lung Cancer Stem Cells to Axitinib-Induced Apoptosis Through Repression of Akt1/Wnt Signaling

Meng Wang^*1, Xin Wang^†1, Yuan Li^‡1, Qiang Xiao^§, Xiao-Hai Cui^*, Guo-Dong Xiao^*, Ji-Chang Wang^¶, Chong-Wen Xu^#, Hong Ren^*, Dapeng Liu^*

* Department of Thoracic Surgery and Oncology, the Second Department of Thoracic Surgery, Cancer Center, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
† Department of Gastroenterology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
‡ School of Humanities and Social Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China § Department of Medical Oncology, Cancer Center, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
¶ Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
# Department of Otorhinolaryngology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China

Oncology Research 2019, 27(9), 987-995. https://doi.org/10.3727/096504018X15424918479652

Abstract

The aim of this study was to investigate the potential biological activities of nutlin-3 in the regulation of growth and proliferation of non-small cell lung cancer (NSCLC) stem cells (CSCs), which may help in sensitizing to axitinib-induced apoptosis. Nutlin-3 induction of p53 expression was used to test its role in controlling the cell division pattern and apoptosis of NSCLC cells. A549 cells and H460 cells were pretreated with nutlin-3 and then treated with either an Akt1 activator or shRNA-GSK3 , to investigate the potential role of p53 sensitization in the biological effects of axitinib. We also determined the expression levels of GSK3 and p-Akt1 in patients with NSCLC and determined their potential association with survival data using Kaplan–Meier plots and CBIOTAL. Increased p53 expression stimulated the induction of apoptosis by axitinib and promoted asymmetric cell division (ACD) of NSCLC CSCs. The repression of Akt phosphorylation induced by nutlin-3 promoted the ACD of lung CSCs, decreasing the proportion of the stem cell population. In addition to the induction of apoptosis by axitinib through inhibition of Wnt signaling, nutlin-3 treatment further enhanced axitinib-induced apoptosis by inhibiting Akt1/GSK3 /Wnt signaling. The low expression of GSK3 and increased expression of p-Akt in patients with NSCLC were closely associated with the development of NSCLC. TP53 stimulates the induction of apoptosis in NSCLC by axitinib and the ACD of lung CSCs through its regulatory effects on the p53/Akt/GSK3 pathways.

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