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6-Shogaol from ginger shows anti-tumor effect in cervical carcinoma via PI3K/Akt/mTOR pathway

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Abstract

Purpose

6-Shogaol, an active phenolic compound from ginger (Zingiber officinale), can inhibit the growth of a variety of human cancer cells. Nevertheless, its underlying molecular mechanisms in cervical cancer remain unclear. In this study, we systematically examine the inhibitory effect of 6-shogaol on cervical cancer in vitro and in vivo.

Methods

Cell proliferation was assessed by CCK8 assay and colony formation assay in HeLa and SiHa cells. We analyzed cell cycle and apoptosis through flow cytometry. GFP-LC3 puncta and transmission electron microscopy were used to observe autophagic bodies. Wound-healing assay and transwell assay were used for evaluating the migration of cells. Western blot was applied to detect protein expression levels.

Results

6-Shogaol could suppress cell proliferation and migration, cause cell cycle arrest in the G2/M phase in HeLa and SiHa cells. Moreover, 6-shogaol triggered the apoptosis process through the mitochondrial pathway by downregulating the expression levels of p-PI3K, p-Akt and p-mTOR. Further research indicated that the induction of apoptosis by 6-shogaol was remarkably decreased after the treatment of ROS scavenger and PI3K agonist. Additionally, 6-shogaol increased the number of LC3-positive puncta and autophagic bodies per cell in both HeLa and SiHa cells. Pretreatment of cells with Bafilomycin A1, an autophagy inhibitor, accelerated 6-shogaol mediated cell apoptosis, suggesting that induction of autophagy by 6-shogaol is suppressive to apoptosis. Furthermore, in vivo data revealed that 6-shogaol significantly inhibited tumor growth and cell proliferation in tumor tissues.

Conclusion

These findings suggested that 6-shogaol could be developed as a functional food ingredient, which is potentially used as therapeutic agents for patients with cervical cancer.

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Abbreviations

PI3K:

Phosphatidylinositol 3-kinase

AKT:

Protein kinase B

mTOR:

Mammalian target of rapamycin

CCK:

Cell-counting kit

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

FBS:

Fetal bovine serum

HRP:

Horseradish peroxidase

PBS:

Phosphate-buffered saline

Δψm:

Mitochondrial membrane potential

PCNA:

Proliferating cell nuclear antigen

EDTA:

Ethylene dinitrilotetraacetic acid

NAC:

N-Acetyl-cysteine

PARP:

Poly ADP-ribose polymerase

IGF-1:

Insulin-like growth factors-1

ROS:

Reactive oxygen species

DCFH-DA:

2, 7-dichlorofluorescein diacetate

CDK:

Cyclin-dependent kinases

SDS-PAGE:

Sulfate-polyacrylamide gel electrophoresis

Cdc:

Cell division cycle

H&E:

Hematoxylin and eosin

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Acknowledgements

This research was supported by State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (Grant No. GTZK201810); Key laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education (Grant No. GKE2018-KF01); Guangdong Academic of Sciences Special Project of Science and Technology Development (Grant No. 2016GDASRC-0104); and Guangdong Key Laboratory of Animal Conservation and Resource Utilization (Grant No. GIABR-KF201901); The Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology & Business University (BTBU); Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine) (Grant No. WDCM2019012).

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Authors and Affiliations

  1. College of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, Guangxi, People’s Republic of China

    Xiao-Dong Pei, Zhi-Long He & Li-He Jiang

  2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People’s Republic of China

    Xiao-Dong Pei & Li-He Jiang

  3. Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangdong, 510260, People’s Republic of China

    Hong-Liang Yao

  4. Beijing Higher Institution Engineering Research Center of Food Additives and Ingredients, Beijing Technology and Business University-BTBU, Beijing, 100048, People’s Republic of China

    Jun-Song Xiao

  5. School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China

    Lan Li, Jian-Zhong Gu, Pei-Zhao Shi, Jin-Hua Wang & Li-He Jiang

  6. West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Jin-Hua Wang

  7. Medical College, Guangxi University, Nanning, 530004, Guangxi, People’s Republic of China

    Li-He Jiang

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  1. Xiao-Dong Pei
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  2. Zhi-Long He
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  4. Jun-Song Xiao
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  5. Lan Li
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Contributions

XDP: Conceived, Designed, Data curation, Formal analysis, Writing-review & editing. ZLH: Data curation and Formal analysis. HLY: Data curation and Writing-review & editing. JSX: Writing-review & editing. LL: Data curation and Formal analysis. JZG: Data curation and Formal analysis. PZS: Data curation and Formal analysis. JHW: Data curation, Formal analysis and Writing-review and editing. LHJ: Conceived, Designed, Data curation, Formal analysis and Writing-review and editing; Undertake related research programs and fund this study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Li-He Jiang.

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Pei, XD., He, ZL., Yao, HL. et al. 6-Shogaol from ginger shows anti-tumor effect in cervical carcinoma via PI3K/Akt/mTOR pathway. Eur J Nutr 60, 2781–2793 (2021). https://doi.org/10.1007/s00394-020-02440-9

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