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-1α (HIF-1α) 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-1α pathway might, at least in part, contribute to the radiosensitizing effect of MCL. Further study showed that MCL could accelerate the degradation of HIF-1α 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-1α expression. These results suggest MCL effectively sensitizes p53-deficient NSCLC cells to IR in a manner of inhibiting the HIF-1α pathway via promoting HIF-1α degradation, and p53 played a negative role in MCL-induced HIF-1α degradation.
Highlights
Lung cancer is the leading cause of cancer incidence and mortality worldwide, and non-small-cell lung cancer (NSCLC) is the most common histological subtype of lung cancers [1,2]
We found that MCL inhibited the growth of NSCLC cells (H1299 and Calu-1) in a concentration-dependent manner
DMAPT sensitized NSCLC to IR by inhibiting NF-κB activation and blocking DSB repair [34], whereas the activation of the NF-κB pathway and DSBs repair induced by IR were not affected by MCL in the present study (Figures S2 and S3)
Summary
Lung cancer is the leading cause of cancer incidence and mortality worldwide, and non-small-cell lung cancer (NSCLC) is the most common histological subtype of lung cancers [1,2]. Previous researches have shown that radiation could increase the level of HIF-1α protein in a subset of radioresistant lung cancer cell lines [13]. Elevated HIF-1α protein expression promoted the secretion of vascular endothelial growth factor (VEGF), which mediated tumor-protective response to radiotherapy via vascular protection or inhibiting IR-induced apoptosis by upregulating anti-apoptosis protein, Bcl-2 [13,14,15]. Hypoxia-induced HIF-1α activated the expression of glucose transporter-1 (GLUT-1), which conferred the enhanced tumor antioxidant capacity linking to radioresistance through initiating a glycolytic tumor metabolism [16]. PTL selectively exhibits a radiosensitizing effect on prostate cancer cells, but not normal prostate epithelial cells by activating NADPH oxidase and it mediates intense oxidative stress [27]. The radiosensitizing effect of MCL on NSCLC and the possible underlying mechanisms are still not known
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