Micheliolide Enhances Radiosensitivities of p53-Deficient Non-Small-Cell Lung Cancer via Promoting HIF-1? Degradation.

ABSTRACT: Micheliolide (MCL) has shown promising anti-inflammatory and anti-tumor efficacy. However, whether and how MCL enhances the sensitivity of non-small-cell lung cancer (NSCLC) to radiotherapy are still unknown. In the present paper, we found that MCL exerted a tumor cell killing effect on NSCLC cells in a dose-dependent manner, and MCL strongly sensitized p53-deficient NSCLC cells, but not the cells with wild-type p53 to irradiation (IR). Meanwhile, MCL markedly inhibited the expression of hypoxia-inducible factor-1? (HIF-1?) after IR and hypoxic exposure in H1299 and Calu-1 cells rather than in H460 cells. Consistently, radiation- or hypoxia-induced expression of vascular endothelial growth factor (VEGF) was also significantly inhibited by MCL in H1299 and Calu-1 cells, but not in H460 cells. Therefore, inhibition of the HIF-1? pathway might, at least in part, contribute to the radiosensitizing effect of MCL. Further study showed that MCL could accelerate the degradation of HIF-1? through the ubiquitin-proteosome system. In addition, the transfection of wild-type p53 into p53-null cells (H1299) attenuated the effect of MCL on inhibiting HIF-1? expression. These results suggest MCL effectively sensitizes p53-deficient NSCLC cells to IR in a manner of inhibiting the HIF-1? pathway via promoting HIF-1? degradation, and p53 played a negative role in MCL-induced HIF-1? degradation.

SUBMITTER: Kong P 

PROVIDER: S-EPMC7247679 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature