Dehydrodiisoeugenol Inhibits Colorectal Cancer Growth by Endoplasmic Reticulum Stress-induced Autophagic Pathways

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2021 Apr 11

PMID 33838688

Citations 23

Authors

Changhong Li

Kui Zhang

Guangzhao Pan

Haoyan Ji

Chongyang Li

Xiaowen Wang

Xin Hu

Ruochen Liu

Longfei Deng

Yi Wang

Liqun Yang

Hongjuan Cui

Affiliations

Soon will be listed here.

Abstract

Background: Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated.

Methods: In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo.

Results: Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models.

Conclusions: Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

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References

Rogov V, Dotsch V, Johansen T, Kirkin V . Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell. 2014; 53(2):167-78. DOI: 10.1016/j.molcel.2013.12.014. View

Zhang Z, Zhou L, Xie N, Nice E, Zhang T, Cui Y . Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020; 5(1):113. PMC: 7331117. DOI: 10.1038/s41392-020-00213-8. View

Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42. PMC: 2696814. DOI: 10.1016/j.cell.2007.12.018. View

Xu D, Wang Z, Chen Y . Two-layer regulation of PAQR3 on ATG14-linked class III PtdIns3K activation upon glucose starvation. Autophagy. 2016; 12(6):1047-8. PMC: 4922432. DOI: 10.1080/15548627.2016.1163459. View

Li T, Su L, Zhong N, Hao X, Zhong D, Singhal S . Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells. Autophagy. 2013; 9(7):1057-68. PMC: 3722315. DOI: 10.4161/auto.24632. View

Wang F, Jiang J, Hu S, Ma H, Zhu H, Tong Q . Secondary metabolites from endophytic fungus Chaetomium sp. induce colon cancer cell apoptotic death. Fitoterapia. 2017; 121:86-93. DOI: 10.1016/j.fitote.2017.06.021. View

Zhou L, Zhang Z, Huang Z, Nice E, Zou B, Huang C . Revisiting cancer hallmarks: insights from the interplay between oxidative stress and non-coding RNAs. Mol Biomed. 2022; 1(1):4. PMC: 8603983. DOI: 10.1186/s43556-020-00004-1. View

Pal M, Febbraio M, Whitham M . From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol. 2014; 92(4):331-9. DOI: 10.1038/icb.2014.16. View

Smeby J, Sveen A, Merok M, Danielsen S, Eilertsen I, Guren M . CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer. Ann Oncol. 2018; 29(5):1227-1234. PMC: 5961317. DOI: 10.1093/annonc/mdy085. View

10.

Zhang K, Fu G, Pan G, Li C, Shen L, Hu R . Demethylzeylasteral inhibits glioma growth by regulating the miR-30e-5p/MYBL2 axis. Cell Death Dis. 2018; 9(10):1035. PMC: 6180101. DOI: 10.1038/s41419-018-1086-8. View

11.

Codogno P, Meijer A . Autophagy: a potential link between obesity and insulin resistance. Cell Metab. 2010; 11(6):449-51. DOI: 10.1016/j.cmet.2010.05.006. View

12.

Liu J, Wang T, Creighton C, Wu S, Ray M, Janardhan K . JNK represses Lkb-deficiency-induced lung squamous cell carcinoma progression. Nat Commun. 2019; 10(1):2148. PMC: 6517592. DOI: 10.1038/s41467-019-09843-1. View

13.

Chen X, Cao Z, Liao L, Liu Z, Du J . Application of serum pharmacology in evaluating the antitumor effect of Fuzheng Yiliu Decoction from Chinese medicine. Chin J Integr Med. 2013; 20(6):450-5. DOI: 10.1007/s11655-013-1544-1. View

14.

Daniels M, Bannon S, Mork M . Frequency of Germline BRCA1/2 Mutations in Unselected Patients With Colorectal Cancer. J Clin Oncol. 2017; 35(22):2588. DOI: 10.1200/JCO.2017.72.7222. View

15.

Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G . Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 2003; 63(5):1138-43. View

16.

Li C, Deng C, Pan G, Wang X, Zhang K, Dong Z . Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer. J Exp Clin Cancer Res. 2020; 39(1):230. PMC: 7602321. DOI: 10.1186/s13046-020-01743-3. View

17.

Winawer S, Fletcher R, Miller L, Godlee F, Stolar M, Mulrow C . Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology. 1997; 112(2):594-642. DOI: 10.1053/gast.1997.v112.agast970594. View

18.

Sepulveda A, Hamilton S, Allegra C, Grody W, Cushman-Vokoun A, Funkhouser W . Molecular Biomarkers for the Evaluation of Colorectal Cancer. Am J Clin Pathol. 2017; 147(3):221-260. PMC: 7263311. DOI: 10.1093/ajcp/aqw209. View

19.

Rabinowitz J, White E . Autophagy and metabolism. Science. 2010; 330(6009):1344-8. PMC: 3010857. DOI: 10.1126/science.1193497. View

20.

Lach-Trifilieff E, Minetti G, Sheppard K, Ibebunjo C, Feige J, Hartmann S . An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol Cell Biol. 2013; 34(4):606-18. PMC: 3911487. DOI: 10.1128/MCB.01307-13. View