Diallyl Disulfide Inhibits Proliferation, Epithelial-mesenchymal Transition, and Invasion Through RORα-mediated Downregulation of Wnt1/β-catenin Pathway in Gastric Cancer Cells

Overview

Journal J Food Drug Anal

Specialties Nutritional Sciences
Pharmacology
Toxicology

Date 2024 Dec 12

PMID 39666293

Authors

Jian Su

Hui He

Yu-Kun Li

Hong Xia

Fang Liu

Ying Zeng

Xi Zeng

Hui Ling

Bo Su

Qi Su

Affiliations

Soon will be listed here.

Abstract

Overactivation of Wnt/β-catenin pathway due to dysfunction of retinoid-related orphan receptor α (RORα) is related to cancer development and progression. Diallyl disulfide (DADS), an active component of garlic, has been reported in our previous study for upregulation of RORα expression in gastric cancer (GC) cells. It remains to be elucidated the role and mechanism of RORα in DADS against GC. This study revealed that DADS treatment resulted in reduced expression levels of Wnt1, β-catenin, TCF-4, intranuclear β-catenin and p-β-catenin in GC cells, concomitant with the compromised expression of β-catenin target genes (Axin, c-Jun, and c-Myc). RORα overexpression augmented DADS-induced downregulation of Wnt1/β-catenin pathway, G2/M phase arrest, and cell growth inhibition in vitro and in vivo. Contrarily, knockdown of RORα attenuated these effects of DADS. Interestingly, DADS induced an increase in the binding of RORα to β-catenin, which may lead to reduction of β-catenin phosphorylation and nuclear translocation. This interplay modulated by DADS may affect β-catenin target gene expression for that the opposite results were observed in DADS-treated RORα knockdown and overexpression cells. DADS caused a decrease in vimentin, snail and MMP-9, as well as an increase in E-cadherin and TIMP3 expression, which restricted epithelial-mesenchymal transition (EMT), migration, and invasion. The aforementioned effects of DADS were weakened simultaneously when the suppression of DADS on the Wnt1/β-catenin pathway was resisted by knockdown of RORα. In contrast, overexpression of RORα enhanced the effects of DADS. Therefore, RORα-mediated downregulation of Wnt1/β-catenin pathway could undertake an important role in anticancer activity of DADS against GC cell proliferation, EMT, migration, and invasion.

References

Saha S, Choi H, Kim B, Dayem A, Yang G, Kim K . KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties. Oncogene. 2016; 36(3):332-349. PMC: 5270332. DOI: 10.1038/onc.2016.221. View

Su B, Su J, Zeng Y, Ding E, Liu F, Tan T . Diallyl disulfide inhibits TGF‑β1‑induced upregulation of Rac1 and β‑catenin in epithelial‑mesenchymal transition and tumor growth of gastric cancer. Oncol Rep. 2018; 39(6):2797-2806. DOI: 10.3892/or.2018.6345. View

Pethe V, Charames G, Bapat B . Rac1b recruits Dishevelled and β-catenin to Wnt target gene promoters independent of Wnt3A stimulation. Int J Oncol. 2011; 39(4):805-10. DOI: 10.3892/ijo.2011.1066. View

Yang L, Ying X, Liu S, Lyu G, Xu Z, Zhang X . Gastric cancer: Epidemiology, risk factors and prevention strategies. Chin J Cancer Res. 2021; 32(6):695-704. PMC: 7797232. DOI: 10.21147/j.issn.1000-9604.2020.06.03. View

Bo S, Hui H, Li W, Hui L, Hong X, Lin D . Chk1, but not Chk2, is responsible for G2/M phase arrest induced by diallyl disulfide in human gastric cancer BGC823 cells. Food Chem Toxicol. 2014; 68:61-70. DOI: 10.1016/j.fct.2014.03.007. View

Lee J, Kim I, Kim H, Lee J, Kim K, Yim H . RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer. Mol Cell. 2010; 37(2):183-95. DOI: 10.1016/j.molcel.2009.12.022. View

Zhao J, Luo Y, Jiang Y, He D, Wu C . Knockdown of β-Catenin through shRNA cause a reversal of EMT and metastatic phenotypes induced by HIF-1α. Cancer Invest. 2011; 29(6):377-82. DOI: 10.3109/07357907.2010.512595. View

Su B, Su J, Zeng Y, Liu F, Xia H, Ma Y . Diallyl disulfide suppresses epithelial-mesenchymal transition, invasion and proliferation by downregulation of LIMK1 in gastric cancer. Oncotarget. 2016; 7(9):10498-512. PMC: 4891135. DOI: 10.18632/oncotarget.7252. View

Ling H, Lu L, He J, Xiao G, Jiang H, Su Q . Diallyl disulfide selectively causes checkpoint kinase-1 mediated G2/M arrest in human MGC803 gastric cancer cell line. Oncol Rep. 2014; 32(5):2274-82. DOI: 10.3892/or.2014.3417. View

10.

Almatroodi S, Alsahli M, Almatroudi A, Rahmani A . Garlic and its Active Compounds: A Potential Candidate in The Prevention of Cancer by Modulating Various Cell Signalling Pathways. Anticancer Agents Med Chem. 2019; 19(11):1314-1324. DOI: 10.2174/1871520619666190409100955. View

11.

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

12.

Zhu G, Wang Y, Huang B, Liang J, Ding Y, Xu A . A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells. Oncogene. 2011; 31(8):1001-12. DOI: 10.1038/onc.2011.294. View

13.

Yue Z, Guan X, Chao R, Huang C, Li D, Yang P . Diallyl Disulfide Induces Apoptosis and Autophagy in Human Osteosarcoma MG-63 Cells through the PI3K/Akt/mTOR Pathway. Molecules. 2019; 24(14). PMC: 6681087. DOI: 10.3390/molecules24142665. View

14.

Huang J, Fu Y, Gan W, Liu G, Zhou P, Zhou C . Hepatic stellate cells promote the progression of hepatocellular carcinoma through microRNA-1246-RORα-Wnt/β-Catenin axis. Cancer Lett. 2020; 476:140-151. DOI: 10.1016/j.canlet.2020.02.012. View

15.

Tang H, Kong Y, Guo J, Tang Y, Xie X, Yang L . Diallyl disulfide suppresses proliferation and induces apoptosis in human gastric cancer through Wnt-1 signaling pathway by up-regulation of miR-200b and miR-22. Cancer Lett. 2013; 340(1):72-81. DOI: 10.1016/j.canlet.2013.06.027. View

16.

Kim H, Lee J, Lee G, Bhin J, Oh S, Kim K . DNA damage-induced RORα is crucial for p53 stabilization and increased apoptosis. Mol Cell. 2011; 44(5):797-810. DOI: 10.1016/j.molcel.2011.09.023. View

17.

Zheng X, Wu K, Liao S, Pan Y, Sun Y, Chen X . MicroRNA-transcription factor network analysis reveals miRNAs cooperatively suppress RORA in oral squamous cell carcinoma. Oncogenesis. 2018; 7(10):79. PMC: 6174157. DOI: 10.1038/s41389-018-0089-8. View

18.

Du J, Xu R . RORα, a potential tumor suppressor and therapeutic target of breast cancer. Int J Mol Sci. 2013; 13(12):15755-66. PMC: 3546659. DOI: 10.3390/ijms131215755. View

19.

Liu G, Yang Z, Zhou P, Zhou C, Guan R, Sun B . ROR-α-1 inhibits the proliferation, invasion, and migration of hepatocellular carcinoma MHCC97H via downregulation of chemokine CXCL5. Cytokine. 2020; 129:155004. DOI: 10.1016/j.cyto.2020.155004. View

20.

Su B, Su J, He H, Wu Y, Xia H, Zeng X . Identification of potential targets for diallyl disulfide in human gastric cancer MGC-803 cells using proteomics approaches. Oncol Rep. 2015; 33(5):2484-94. DOI: 10.3892/or.2015.3859. View