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

Anhui Province Key Laboratory of Medical Physics and Technology/Center of Medical Physics and Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei 230031, China

Science Island Branch of Graduate School, University of Science and Technology of China, Hefei 230026, China

Department of Physics, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong 999077, Hong Kong

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State Key Laboratory in Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong 999077, Hong Kong

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Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou 215123, China

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2020, 21(9), 3392; https://doi.org/10.3390/ijms21093392

Received: 30 April 2020 / Revised: 8 May 2020 / Accepted: 8 May 2020 / Published: 11 May 2020

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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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. View Full-Text

Keywords: micheliolide; radiosensitizer; hypoxia-inducible factor-1α; vascular endothelial growth factor; p53

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Kong, P.; Yu, K.N.; Yang, M.; Almahi, W.A.; Nie, L.; Chen, G.; Han, W. Micheliolide Enhances Radiosensitivities of p53-Deficient Non-Small-Cell Lung Cancer via Promoting HIF-1α Degradation. Int. J. Mol. Sci. 2020, 21, 3392. https://doi.org/10.3390/ijms21093392

AMA Style

Kong P, Yu KN, Yang M, Almahi WA, Nie L, Chen G, Han W. Micheliolide Enhances Radiosensitivities of p53-Deficient Non-Small-Cell Lung Cancer via Promoting HIF-1α Degradation. International Journal of Molecular Sciences. 2020; 21(9):3392. https://doi.org/10.3390/ijms21093392

Chicago/Turabian Style

Kong, Peizhong, K.N. Yu, Miaomiao Yang, Waleed A. Almahi, Lili Nie, Guodong Chen, and Wei Han. 2020. "Micheliolide Enhances Radiosensitivities of p53-Deficient Non-Small-Cell Lung Cancer via Promoting HIF-1α Degradation" International Journal of Molecular Sciences 21, no. 9: 3392. https://doi.org/10.3390/ijms21093392

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

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