Isoliensinine induces cervical cancer cell cycle arrest and apoptosis by inhibiting the AKT/GSK3α pathway

Li,Hong-Li; Cheng,Yan; Zhou,Zi-Wei; Long,Hui-Zhi; Luo,Hong-Yu; Wen,Dan-Dan; Cheng,Lin; Gao,Li-Chen

doi:10.3892/ol.2021.13126

Isoliensinine induces cervical cancer cell cycle arrest and apoptosis by inhibiting the AKT/GSK3α pathway

Authors:
- Hong-Li Li
- Yan Cheng
- Zi-Wei Zhou
- Hui-Zhi Long
- Hong-Yu Luo
- Dan-Dan Wen
- Lin Cheng
- Li-Chen Gao
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Affiliations: Department of Pharmacy, Cancer Institute, Phase I Clinical Trial Centre, Changsha Central Hospital Affiliated to University of South China, School of Pharmacy, University of South China, Changsha, Hunan 410000, P.R. China, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China
Published online on: November 9, 2021 https://doi.org/10.3892/ol.2021.13126
Article Number: 8
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Isoliensinine is a bis‑benzylisoquinoline alkaloid that can be isolated from the lotus Nelumbo nucifera Gaertn. It has been reported to exert a variety of anti‑cancer properties. In the present study, the potential effects of isoliensinine on cervical cancer Siha, HeLa, Caski and C33A cell lines were investigated by using Cell Counting Kit‑8 (CCK‑8), flow cytometry, western blotting and reverse transcription‑PCR (RT‑PCR) to measure cell proliferation, the cell cycle and apoptosis, in addition to elucidating the underlying molecular mechanism. Protein levels of p21, CDK2, Cyclin E, Mcl‑1, cleaved Caspase‑9, AKT, phosphorylated‑AKT, glycogen synthase kinase (Gsk)3α, PTEN, and mRNA levels of p21, p15, p27, CDK2, CDK4, Cyclin E, Cyclin D, Gsk3α, Gsk3β and PTEN were measured. Molecular docking assays were used to calculate the strength of binding of isoliensinine to AKT using AutoDock 4.0. Isoliensinine was found to induce cell cycle arrest at the G₀/G₁ phase by upregulating p21 expression and downregulating CDK2 and cyclin E in cervival cancer cells. In addition, in previous research, isoliensinine promoted cell apoptosis by downregulating myeloid‑cell leukemia 1 expression and activating caspase‑9. Upstream, isoliensinine significantly downregulated AKT (S473) phosphorylation and GSK3α expression in a dose‑ and time‑dependent manner. The AKT inhibitor AKTi‑1/2 enhanced the function of isoliensinine on cell cycle arrest and apoptosis through the AKT/GSK3α pathway. AutoDock analysis showed that isoliensinine can bind to the AKT protein. These findings suggest that isoliensinine can induce cervical cancer cell cycle arrest and apoptosis by inhibiting the AKT/GSK3α pathway, which represents a novel strategy for the treatment of cervical cancer.

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