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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

Open Access 01-12-2020 | Gastric Cancer | Research

Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer

Authors: Chongyang Li, Chaowei Deng, Guangzhao Pan, Xue Wang, Kui Zhang, Zhen Dong, Gaichao Zhao, Mengqin Tan, Xiaosong Hu, Shaomin Shi, Juan Du, Haoyan Ji, Xiaowen Wang, Liqun Yang, Hongjuan Cui

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

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Abstract

Background

Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment.

Methods

The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).

Results

In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14–1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer.

Conclusions

The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.
Appendix
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Literature
1.
EC S, M N, HI G, van Grieken NC, F L. Gastric cancer. Lancet (London, England). 2020;396:635–48.
2.
3.
Li W, Zhang X, Wu F, et al. Gastric cancer-derived mesenchymal stromal cells trigger M2 macrophage polarization that promotes metastasis and EMT in gastric cancer. Cell Death Dis. 2019;10:918.PubMedPubMedCentral
4.
Montagnani F, Crivelli F, Aprile G, et al. Long-term survival after liver metastasectomy in gastric cancer: systematic review and meta-analysis of prognostic factors. Cancer Treat Rev. 2018;69:11–20.PubMed
5.
Kitayama J, Ishigami H, Yamaguchi H, et al. Treatment of patients with peritoneal metastases from gastric cancer. Ann Gastroenterol Surg. 2018;2:116–23.PubMedPubMedCentral
6.
Song Y, Wang Y, Tong C, et al. A unified model of the hierarchical and stochastic theories of gastric cancer. Br J Cancer. 2017;116:973–89.PubMedPubMedCentral
7.
Jakubek M, Kejik Z, Kaplanek R, et al. Strategy for improved therapeutic efficiency of curcumin in the treatment of gastric cancer. Biomed Pharmacother. 2019;118:109278.PubMed
8.
Wu Q, Yang Z, Nie Y, Shi Y, Fan D. Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett. 2014;347:159–66.PubMed
9.
Wang JH, Du JP, Zhang YH, et al. Dynamic changes and surveillance function of prion protein expression in gastric cancer drug resistance. World J Gastroenterol. 2011;17:3986–93.PubMedPubMedCentral
10.
Leist M, Jaattela M. Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol. 2001;2:589–98.PubMed
11.
Kaufmann SH, Gores GJ. Apoptosis in cancer: cause and cure. BIOESSAYS. 2000;22:1007–17.PubMed
12.
Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108:153–64.PubMed
13.
Park H, Cho SY, Kim H, et al. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer. Proc Natl Acad Sci U S A. 2015;112:12492–7.PubMedPubMedCentral
14.
Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47–59.PubMed
15.
16.
Belmar J, Fesik SW. Small molecule mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther. 2015;145:76–84.PubMed
17.
Chen L, Willis SN, Wei A, et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005;17:393–403.PubMed
18.
Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017;16:273–84.PubMed
19.
Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421–8.PubMed
20.
Zhao Y, He J, Li J, et al. Demethylzeylasteral inhibits cell proliferation and induces apoptosis through suppressing MCL1 in melanoma cells. Cell Death Dis. 2017;8:e3133.PubMedPubMedCentral
21.
Shoemaker AR, Mitten MJ, Adickes J, et al. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res. 2008;14:3268–77.PubMed
22.
van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if mcl-1 is neutralized. Cancer Cell. 2006;10:389–99.PubMedPubMedCentral
23.
Akgul C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 2009;66:1326–36.PubMed
24.
Quinn BA, Dash R, Azab B, et al. Targeting mcl-1 for the therapy of cancer. Expert Opin Investig Drugs. 2011;20:1397–411.PubMedPubMedCentral
25.
Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–8.PubMed
26.
Lamoral-Theys D, Decaestecker C, Mathieu V, et al. Lycorine and its derivatives for anticancer drug design. Mini-Rev Med Chem. 2010;10:41–50.PubMed
27.
Cedron JC, Gutierrez D, Flores N, Ravelo AG, Estevez-Braun A. Synthesis and antiplasmodial activity of lycorine derivatives. Bioorg Med Chem. 2010;18:4694–701.PubMed
28.
Nair JJ, van Staden J. Acetylcholinesterase inhibition within the lycorine series of Amaryllidaceae alkaloids. Nat Prod Commun. 2012;7:959–62.PubMed
29.
Cao Z, Yu D, Fu S, et al. Lycorine hydrochloride selectively inhibits human ovarian cancer cell proliferation and tumor neovascularization with very low toxicity. Toxicol Lett. 2013;218:174–85.PubMed
30.
Zhang K, Fu G, Pan G, et al. Demethylzeylasteral inhibits glioma growth by regulating the miR-30e-5p/MYBL2 axis. Cell Death Dis. 2018;9:1035.PubMedPubMedCentral
31.
Zhao Y, He J, Li Y, Lv S, Cui H. NUSAP1 potentiates chemoresistance in glioblastoma through its SAP domain to stabilize ATR. Signal Transduct Target Ther. 2020;5:44.PubMedPubMedCentral
32.
Cao J, Zhao E, Zhu Q, et al. Tubeimoside-1 inhibits Glioblastoma growth, migration, and invasion via inducing Ubiquitylation of MET. Cells-Basel. 2019;8:774.
33.
Zhang G, Zhu Q, Fu G, et al. TRIP13 promotes the cell proliferation, migration and invasion of glioblastoma through the FBXW7/c-MYC axis. Br J Cancer. 2019;121:1069–78.PubMedPubMedCentral
34.
Jin ZJ. Addition in drug combination. Acta Pharmacol Sin. 1980;1:70–6.
35.
Likui W, Qun L, Wanqing Z, et al. Prognostic role of myeloid cell leukemia-1 protein (mcl-1) expression in human gastric cancer. J Surg Oncol. 2009;100:396–400.PubMed
36.
Ramsey HE, Fischer MA, Lee T, et al. A novel MCL1 inhibitor combined with Venetoclax rescues Venetoclax-resistant acute Myelogenous leukemia. Cancer Discov. 2018;8:1566–81.PubMedPubMedCentral
37.
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.PubMed
38.
Sieghart W, Losert D, Strommer S, et al. Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol. 2006;44:151–7.PubMed
39.
Bierbrauer A, Jacob M, Vogler M, Fulda S. A direct comparison of selective BH3-mimetics reveals BCL-XL, BCL-2 and MCL-1 as promising therapeutic targets in neuroblastoma. Br J Cancer. 2020;122:1544–51.PubMedPubMedCentral
40.
Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006;21:749–60.PubMed
41.
Tong J, Wang P, Tan S, et al. Mcl-1 degradation is required for targeted therapeutics to eradicate Colon Cancer cells. Cancer Res. 2017;77:2512–21.PubMedPubMedCentral
42.
Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of mcl-1 and regulates apoptosis. CELL. 2005;121:1085–95.PubMed
43.
Ding Q, He X, Hsu JM, et al. Degradation of mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol. 2007;27:4006–17.PubMed
44.
Inuzuka H, Shaik S, Onoyama I, et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. NATURE. 2011;471:104–9.PubMedPubMedCentral
45.
Wertz IE, Kusam S, Lam C, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471:110–4.PubMed
46.
Wu X, Luo Q, Zhao P, et al. JOSD1 inhibits mitochondrial apoptotic signalling to drive acquired chemoresistance in gynaecological cancer by stabilizing MCL1. Cell Death Differ. 2020;27:55–70.PubMed
47.
Wu X, Luo Q, Zhao P, et al. MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer. Proc Natl Acad Sci U S A. 2019;116:2961–6.PubMedPubMedCentral
48.
Zhang S, Zhang M, Jing Y, et al. Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors. Nat Commun. 2018;9:215.PubMedPubMedCentral
49.
Schwickart M, Huang X, Lill JR, et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463:103–7.PubMed
50.
Wei SH, Dong K, Lin F, et al. Inducing apoptosis and enhancing chemosensitivity to gemcitabine via RNA interference targeting mcl-1 gene in pancreatic carcinoma cell. Cancer Chemother Pharmacol. 2008;62:1055–64.PubMed
51.
Xia X, Huang C, Liao Y, et al. Inhibition of USP14 enhances the sensitivity of breast cancer to enzalutamide. J Exp Clin Cancer Res. 2019;38:220.PubMedPubMedCentral
Metadata
Title
Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer
Authors
Chongyang Li
Chaowei Deng
Guangzhao Pan
Xue Wang
Kui Zhang
Zhen Dong
Gaichao Zhao
Mengqin Tan
Xiaosong Hu
Shaomin Shi
Juan Du
Haoyan Ji
Xiaowen Wang
Liqun Yang
Hongjuan Cui
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01743-3

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