Introduction of exogenous wild‑type p53 mediates the regulation of oncoprotein�18/stathmin signaling via nuclear factor‑κB in non‑small cell lung cancer NCI‑H1299 cells

Abstract

Our previous studies demonstrated that high expression of oncoprotein 18 (Op18)/stathmin promotes malignant transformation of non-small cell lung cancer NCI-H1299 cells. Investigation of the cellular settings determined that NCI-H1299 cells were genetically p53 deficient. In order to determine whether p53 deficiency is associated with Op18/stathmin-mediated high levels of malignancy, exogenous wild-type p53 (p53 wt) was introduced into NCI-H1299 cells in the present study to observe Op18/stathmin signaling changes and malignant behaviors. The results indicated that p53 downregulated Op18/stathmin expression and phosphorylation at the Ser25 and Ser63 sites in NCI-H1299 cells, and the abilities of proliferation, colony formation and migration in multi-dimensional spaces were simultaneously reduced. Introduction of p53 wt inhibited the expression of the transcription factor nuclear factor-κB (NF-κB), and the activities of the Op18/stathmin upstream kinases cyclin-dependent 2 (CDC2) and extracellular signal-regulated kinase (ERK). Furthermore, blocking of NF-κB signaling decreased CDC2 and ERK activation. Additionally, p53 intervention attenuated the secretion and protein expression of the immune inhibitory cytokine interleukin-10, which was in accordance with the effect of NF-κB signaling inhibition. Further experiments validated that p53 enhanced the sensitivity of NCI-H1299 cells to Taxol through initiating the caspase-3 and-9 intrinsic death pathways, and resulted in cell cycle arrest at the G 1 /S phases. These data indicated that exogenous p53 wt mediates the regulation of Op18/stathmin signaling through the p53-NF-κB-CDC2/ERK-Op18/stathmin pathway, and that p53 deficiency is associated with high malignancy levels of NCI-H1299 cells.

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