β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest

Ruonan Zhang; Ting Pan; Yu Xiang; Mingming Zhang; Jiao Feng; Shuiping Liu; Ting Duan; Peng Chen; Bingtao Zhai; Xiaying Chen; Wengang Wang; Bi Chen; Xuemeng Han; Liuxi Chen; Lili Yan; Ting Jin; Ying Liu; Guohua Li; Xingxing Huang; Wenzheng Zhang; Yitian Sun; Qiujie Li; Qin Zhang; Lvjia Zhuo; Tian Xie; Qibiao Wu; Xinbing Sui

doi:10.3389/fbioe.2020.00378

β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest

Front Bioeng Biotechnol. 2020 May 8:8:378. doi: 10.3389/fbioe.2020.00378. eCollection 2020.

Authors

Ruonan Zhang^{1

2

3}, Ting Pan^{1

2}, Yu Xiang^{1

2}, Mingming Zhang^{1

2}, Jiao Feng^{1

2}, Shuiping Liu^{1

2}, Ting Duan^{1

2}, Peng Chen^{1

2}, Bingtao Zhai^{1

2}, Xiaying Chen^{1

2}, Wengang Wang^{1

2}, Bi Chen^{1

2

3}, Xuemeng Han^{1

2}, Liuxi Chen^{1

2}, Lili Yan^{1

2}, Ting Jin^{1

2}, Ying Liu⁴, Guohua Li^{1

2}, Xingxing Huang^{1

2}, Wenzheng Zhang^{1

2}, Yitian Sun^{1

2}, Qiujie Li^{1

2}, Qin Zhang^{1

2}, Lvjia Zhuo^{1

2}, Tian Xie^{1

2}, Qibiao Wu³, Xinbing Sui^{1

2

3}

Affiliations

¹ Department of Medical Oncology, Holistic Integrative Pharmacy Institutes, The Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, China.
² Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province and Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.
³ State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
⁴ Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.

Abstract

Objective: Colorectal cancer is a malignant tumor of the digestive system with high morbidity and mortality. 5-fluorouracil remains a widely used chemotherapeutic drug in the treatment of advanced colorectal cancer, but chemotherapy drugs are prone to develop drug resistance, p53 deletion or mutation is an important reason for the resistance of colorectal cancer cells to 5-fluorouracil. β-elemene has been proved to have the potential of reverse chemotherapy drug resistance, but the mechanism is unknown. This study aimed to investigate the effect of β-elemene to 5-fluorouracil in drug-resistant p53-deficient colorectal cancer cells HCT116p53^-/-, and determine the possible molecular mechanism of β-elemene to reverse 5-fluorouracil resistance.

Methods: The effect of β-elemene on HCT116p53^-/- cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. The autophagy was detected by western blot, immunofluorescence and transmission electron microscope. Determine the role of Cyclin-related protein Cyclin D3 in β-elemene reversing the resistance of HCT116p53^-/- to 5-fluorouracil was detected by overexpression of Cyclin D3. The effect of β-elemene on the tumorigenic ability of p53-deficient colorectal cancer cells was detected establishing HCT116p53^-/- all line xenograft model.

Results: For p53 wildtype colorectal cancer cells, β-elemene could augment the sensitivity of 5-fluorouracil, for p53-deficient colorectal cancer cells, β-elemene significantly inhibited cell proliferation in a concentration-dependent manner, and reversed the resistance of HCT116p53^-/- to 5-fluorouracil by inducing pro-death autophagy and Cyclin D3-dependent cycle arrest.

Conclusion: β-elemene enhances the sensitivity of p53 wild-type cells to 5-fluorouracil, β-elemene can reverse the resistance of HCT116p53^-/- to 5-fluorouracil by inducing pro-death autophagy and Cyclin D3-dependent cycle arrest in p53-deficient colorectal cancer, which will provide a new method for the treatment of p53 deletion colorectal cancer patients.

Keywords: 5-fluorouracil; autophagy; cell cycle; colorectal cancer; drug resistance; p53; β-elemene.