Tubeimoside I induces autophagy in HepG2 cells by activating the AMP‑activated protein kinase signaling pathway

Ruan,Chengxu; You,Lijuan; Qiu,Yingdong; Cui,Xiao; Wu,Defeng

doi:10.3892/ol.2020.11604

Tubeimoside I induces autophagy in HepG2 cells by activating the AMP‑activated protein kinase signaling pathway

Authors:
- Chengxu Ruan
- Lijuan You
- Yingdong Qiu
- Xiao Cui
- Defeng Wu
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Affiliations: College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350116, P.R. China, College of Bee Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
Published online on: May 13, 2020 https://doi.org/10.3892/ol.2020.11604
Pages: 623-630
Copyright: © Ruan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tubeimoside I (TBMS) is a natural compound with antitumor properties. However, the detailed mechanism underlying the function of TBMS in liver cancer has not been fully elucidated. In the present study, TBMS was shown to suppress cell proliferation and induce S phase cell cycle arrest in HepG2 cells. Furthermore, TBMS treatment induced autophagy, evidenced by autophagosome accumulation, and increased the mRNA expression of Beclin 1 and microtubule‑associated protein 1 light chain 3 (LC3)‑I. However, flow cytometry analysis demonstrated that TBMS exerted no effect on cell apoptosis. Moreover, TBMS increased the phosphorylation of AMP‑activated protein kinase (AMPK) in a concentration‑dependent manner, thereby activating the AMPK signaling pathway. A specific AMPK inhibitor, compound C (CC), caused markedly suppressed TBMS‑induced accumulation of LC3‑II. In addition, the mRNA expression of LC3‑Ι and Beclin 1 was also suppressed in cells treated with TBMS and CC in combination. The results of the present study provide new insights into the role of TBMS in inducing autophagy and support the potential application of TBMS for liver cancer treatment in the clinical setting.

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1	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Tejeda-Maldonado J, García-Juárez I, Aguirre-Valadez J, González-Aguirre A, Vilatobá-Chapa M, Armengol-Alonso A, Escobar-Penagos F, Torre A, Sánchez-Ávila JF and Carrillo-Pérez DL: Diagnosis and treatment of hepatocellular carcinoma: An update. World J Hepatol. 7:362–376. 2015. View Article : Google Scholar : PubMed/NCBI
3	Gomaa AI and Waked I: Recent advances in multidisciplinary management of hepatocellular carcinoma. World J Hepatol. 7:673–687. 2015. View Article : Google Scholar : PubMed/NCBI
4	Janku F, McConkey DJ, Hong DS and Kurzrock R: Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 8:528–539. 2011. View Article : Google Scholar : PubMed/NCBI
5	Wang FZ, Xing L, Tang ZH, Lu JJ, Cui PF, Qiao JB, Jiang L, Jiang HL and Zong L: Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic acid nanoparticles to induce autophagy-mediated liver cancer combination therapy. Mol Pharm. 13:1298–1307. 2016. View Article : Google Scholar : PubMed/NCBI
6	Tong H, Li T, Qiu W and Zhu Z: Claudin-1 silencing increases sensitivity of liver cancer HepG2 cells to 5-fluorouracil by inhibiting autophagy. Oncol Lett. 18:5709–5716. 2019.PubMed/NCBI
7	Mizushima N, Yoshimori T and Levine B: Methods in mammalian autophagy research. Cell. 140:313–326. 2010. View Article : Google Scholar : PubMed/NCBI
8	Baehrecke EH: Autophagy: Dual roles in life and death? Nat Rev Mol Cell Biol. 6:505–510. 2005. View Article : Google Scholar : PubMed/NCBI
9	Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, et al: Autophagy and chemotherapy resistance: A promising therapeutic target for cancer treatment. Cell Death Dis. 4:e8382013. View Article : Google Scholar : PubMed/NCBI
10	Kasai R, Miyakoshi M, Matsumoto K, Nie RL, Zhou J, Morita T and Tanaka O: Tubeimoside I, a new cyclic bisdesmoside from Chinese cucurbitaceous folk medicine ‘tu bei mu’, a tuber of Bolbostemma paniculatum. Chem Pharm Bull (Tokyo). 34:3974–3977. 1986. View Article : Google Scholar : PubMed/NCBI
11	Jia G, Wang Q, Wang R, Deng D, Xue L, Shao N, Zhang Y, Xia X, Zhi F and Yang Y: Tubeimoside-1 induces glioma apoptosis through regulation of Bax/Bcl-2 and the ROS/Cytochrome C/Caspase-3 pathway. Onco Targets Ther. 8:303–311. 2015.PubMed/NCBI
12	Zhang Y, Xu XM, Zhang M, Qu D, Niu HY, Bai X, Kan L and He P: Effects of tubeimoside-1 on the proliferation and apoptosis of BGC823 gastric cancer cells in vitro. Oncol Lett. 5:801–804. 2013. View Article : Google Scholar : PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
14	Abu-Qare AW and Abou-Donia MB: Biomarkers of apoptosis: Release of cytochrome c, activation of caspase-3, induction of 8-hydroxy-2′-deoxyguanosine, increased 3-nitrotyrosine, and alteration of p53 gene. J Toxicol Environ Health B Crit Rev. 4:313–332. 2001. View Article : Google Scholar : PubMed/NCBI
15	Dikic I and Elazar Z: Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 19:349–364. 2018. View Article : Google Scholar : PubMed/NCBI
16	Toh TB, Lim JJ and Chow EK: Epigenetics of hepatocellular carcinoma. Clin Transl Med. 8:132019. View Article : Google Scholar : PubMed/NCBI
17	Seow TK, Liang RC, Leow CK and Chung MC: Hepatocellular carcinoma: From bedside to proteomics. Proteomics. 1:1249–1263. 2001. View Article : Google Scholar : PubMed/NCBI
18	Ferro F, Servais S, Besson P, Roger S, Dumas JF and Brisson L: Autophagy and mitophagy in cancer metabolic remodelling. Semin Cell Dev Biol. 98:129–138. 2019. View Article : Google Scholar : PubMed/NCBI
19	Cheng J, Zhang T, Ji H, Tao K, Guo J and Wei W: Functional characterization of AMP-activated protein kinase signaling in tumorigenesis. Biochim Biophys Acta. 1866:232–251. 2016.PubMed/NCBI
20	Poillet-Perez L and White E: Role of tumor and host autophagy in cancer metabolism. Genes Dev. 33:610–619. 2019. View Article : Google Scholar : PubMed/NCBI
21	Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI
22	Apostolova N, Gomez-Sucerquia LJ, Gortat A, Blas-Garcia A and Esplugues JV: Autophagy as a rescue mechanism in efavirenz-induced mitochondrial dysfunction: A lesson from hepatic cells. Autophagy. 7:1402–1404. 2011. View Article : Google Scholar : PubMed/NCBI
23	Ni HM, Bockus A, Boggess N, Jaeschke H and Ding WX: Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology. 55:222–232. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y and Yoshimori T: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19:5720–5728. 2000. View Article : Google Scholar : PubMed/NCBI