Artematrolide A inhibited cervical cancer cell proliferation via ROS/ERK/mTOR pathway and metabolic shift

Xin-Tian Zhang; Jing Hu; Li-Hua Su; Chang-An Geng; Ji-Jun Chen

doi:10.1016/j.phymed.2021.153707

Artematrolide A inhibited cervical cancer cell proliferation via ROS/ERK/mTOR pathway and metabolic shift

Phytomedicine. 2021 Oct:91:153707. doi: 10.1016/j.phymed.2021.153707. Epub 2021 Aug 13.

Authors

Xin-Tian Zhang¹, Jing Hu², Li-Hua Su¹, Chang-An Geng², Ji-Jun Chen³

Affiliations

¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
² State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People's Republic of China.
³ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China. Electronic address: chenjj@mail.kib.ac.cn.

PMID: 34450376
DOI: 10.1016/j.phymed.2021.153707

Abstract

Background: Artematrolide A (AR-A), a guaianolide dimer isolated from Artemisia atrovirens, demonstrated significant inhibitory effect on three human hepatoma cell lines (HepG2, Huh7 and SMMC7721). The anti-cervical cancer effect and mechanism of this compound have yet to be explored. This study is to reveal the role and mechanisms of artematrolide A on cervical cancer cells, and provide the pharmacological understanding of artematrolide A.

Purpose: To investigate the function and possible mechanism of artematrolide A on cervical cancer cells in vitro.

Methods: HeLa S3 and SiHa cells were treated with artematrolide A at various concentrations. In this study, MTT, colony formation, cell migration and invasion, cell cycle analysis, cell apoptosis, reactive oxygen species (ROS) detection, western blotting, enzyme activity, and lactate production of artematrolide A were evaluated.

Results: Artematrolide A inhibited cell viability, proliferation, migration and invasion in a dose-dependent manner, caused cell cycle arrest in G2/M phase, and induced cell apoptosis via Bcl-2/PARP-1. The mechanism of action of artematrolide A included two aspects: artematrolide A suppressed cell proliferation by activating ROS/ERK/mTOR signaling pathway and promoted glucose metabolism from aerobic glycolysis to mitochondrial respiration by activating pyruvate dehydrogenase complex (PDC) and oxoglutarate dehydrogenase complex (OGDC) via inhibiting the activity of alkaline phosphatases (ALP).

Conclusion: Artematrolide A exhibited a significant cytotoxic activity on cervical cancer cells, induced G2/M cell cycle arrest and apoptosis by activating ROS/ERK/mTOR signaling pathway and promoting metabolic shift from aerobic glycolysis to mitochondrial respiration, which suggested artematrolide A might be a potential agent for the treatment of cervical cancer.

Keywords: Artemisia atrovirens; Cell metabolism; Cervical cancer; ERK pathway.

MeSH terms

Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Female
HeLa Cells
Humans
Reactive Oxygen Species
Signal Transduction / drug effects*
TOR Serine-Threonine Kinases
Uterine Cervical Neoplasms* / drug therapy
Uterine Cervical Neoplasms* / pathology

Substances

Reactive Oxygen Species
MTOR protein, human
TOR Serine-Threonine Kinases