Astaxanthin Inhibits JAK/STAT-3 Signaling to Abrogate Cell Proliferation, Invasion and Angiogenesis in a Hamster Model of Oral Cancer

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Oct 9

PMID 25296162

Citations 56

Authors

J Kowshik

Abdul Basit Baba

Hemant Giri

G Deepak Reddy

Madhulika Dixit

Siddavaram Nagini

Affiliations

Soon will be listed here.

Abstract

Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention.

Citing Articles

Curcumin exerts protective effects against valproic acid-induced testicular damage through modulating the JAK1/STAT-3/IL-6 signaling pathway in rats.

Dokumacioglu E, Iskender H, Kapakin K, Bolat I, Mokhtare B, Omur A Iran J Basic Med Sci. 2025; 28(2):230-236.

PMID: 39850114 PMC: 11756740. DOI: 10.22038/ijbms.2024.76948.16659.

Astaxanthin-loaded PLGA nanoparticles inhibit survival of MKN-45 gastric cancer cell line by modulating JAK2/STAT3/mTOR/PI3K pathway.

YektaKooshali M, SobhZahedi M, Razavi Tousi S, Hamidi M, Modiri L BMC Cancer. 2025; 25(1):44.

PMID: 39780129 PMC: 11715247. DOI: 10.1186/s12885-024-13401-4.

High glucose promotes macrophage switching to the M1 phenotype via the downregulation of STAT-3 mediated autophagy.

Zhao Y, Jiang Y, Wang F, Sun L, Ding M, Zhang L PLoS One. 2024; 19(12):e0314974.

PMID: 39739966 PMC: 11687880. DOI: 10.1371/journal.pone.0314974.

Astaxanthin Co-treatment with Low Dose Methotrexate Increases the Cell Cycle Arrest and Ameliorates the Methotrexate-induced Inflammatory Response in NALM-6.

Moridi N, Najafzadeh M, Sayedi M, Sajjadi S Int J Mol Cell Med. 2024; 13(2):133-146.

PMID: 39184820 PMC: 11344562. DOI: 10.22088/IJMCM.BUMS.13.2.133.

Comparative genomic analysis and optimization of astaxanthin production of Rhodotorula paludigena TL35-5 and Rhodotorula sampaioana PL61-2.

Hoondee P, Phuengjayaem S, Kingkaew E, Rojsitthisak P, Sritularak B, Thompho S PLoS One. 2024; 19(7):e0304699.

PMID: 38995888 PMC: 11244826. DOI: 10.1371/journal.pone.0304699.

References

Ben-Yosef Y, Lahat N, Shapiro S, Bitterman H, Miller A . Regulation of endothelial matrix metalloproteinase-2 by hypoxia/reoxygenation. Circ Res. 2002; 90(7):784-91. DOI: 10.1161/01.res.0000015588.70132.dc. View

Bhatia D, Thoppil R, Mandal A, Samtani K, Darvesh A, Bishayee A . Pomegranate Bioactive Constituents Suppress Cell Proliferation and Induce Apoptosis in an Experimental Model of Hepatocellular Carcinoma: Role of Wnt/ β -Catenin Signaling Pathway. Evid Based Complement Alternat Med. 2013; 2013:371813. PMC: 3625556. DOI: 10.1155/2013/371813. View

Rajendran P, Li F, Shanmugam M, Kannaiyan R, Goh J, Wong K . Celastrol suppresses growth and induces apoptosis of human hepatocellular carcinoma through the modulation of STAT3/JAK2 signaling cascade in vitro and in vivo. Cancer Prev Res (Phila). 2012; 5(4):631-43. DOI: 10.1158/1940-6207.CAPR-11-0420. View

Wang D, Wise M, Li F, Dey M . Phytochemicals attenuating aberrant activation of β-catenin in cancer cells. PLoS One. 2012; 7(12):e50508. PMC: 3513294. DOI: 10.1371/journal.pone.0050508. View

Thiyagarajan P, Senthil Murugan R, Kavitha K, Anitha P, Prathiba D, Nagini S . Dietary chlorophyllin inhibits the canonical NF-κB signaling pathway and induces intrinsic apoptosis in a hamster model of oral oncogenesis. Food Chem Toxicol. 2012; 50(3-4):867-76. DOI: 10.1016/j.fct.2011.12.019. View

Tu Y, Zhong Y, Fu J, Cao Y, Fu G, Tian X . Activation of JAK/STAT signal pathway predicts poor prognosis of patients with gliomas. Med Oncol. 2010; 28(1):15-23. DOI: 10.1007/s12032-010-9435-1. View

Wei D, Le X, Zheng L, Wang L, Frey J, Gao A . Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 2003; 22(3):319-29. DOI: 10.1038/sj.onc.1206122. View

Zgheib A, Lamy S, Annabi B . Epigallocatechin gallate targeting of membrane type 1 matrix metalloproteinase-mediated Src and Janus kinase/signal transducers and activators of transcription 3 signaling inhibits transcription of colony-stimulating factors 2 and 3 in mesenchymal.... J Biol Chem. 2013; 288(19):13378-86. PMC: 3650376. DOI: 10.1074/jbc.M113.456533. View

Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987; 162(1):156-9. DOI: 10.1006/abio.1987.9999. View

10.

Trecul A, Morceau F, Dicato M, Diederich M . Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network. Genes Nutr. 2012; 7(2):111-25. PMC: 3316753. DOI: 10.1007/s12263-012-0281-y. View

11.

Pugh C, Ratcliffe P . Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003; 9(6):677-84. DOI: 10.1038/nm0603-677. View

12.

Lamy S, Akla N, Ouanouki A, Lord-Dufour S, Beliveau R . Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin-6/STAT3 pathway. Exp Cell Res. 2012; 318(13):1586-96. DOI: 10.1016/j.yexcr.2012.04.004. View

13.

Ahmed S, Gogal Jr R, Walsh J . A new rapid and simple non-radioactive assay to monitor and determine the proliferation of lymphocytes: an alternative to [3H]thymidine incorporation assay. J Immunol Methods. 1994; 170(2):211-24. DOI: 10.1016/0022-1759(94)90396-4. View

14.

Maoka T, Tokuda H, Suzuki N, Kato H, Etoh H . Anti-oxidative, anti-tumor-promoting, and anti-carcinogensis activities of nitroastaxanthin and nitrolutein, the reaction products of astaxanthin and lutein with peroxynitrite. Mar Drugs. 2012; 10(6):1391-1399. PMC: 3397447. DOI: 10.3390/md10061391. View

15.

Silver-Morse L, Li W . JAK-STAT in heterochromatin and genome stability. JAKSTAT. 2013; 2(3):e26090. PMC: 3772121. DOI: 10.4161/jkst.26090. View

16.

Song X, Zhang J, Wang M, Liu W, Gu X, Lv C . Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells. Biol Pharm Bull. 2011; 34(6):839-44. DOI: 10.1248/bpb.34.839. View

17.

Prabhu P, Ashokkumar P, Sudhandiran G . Antioxidative and antiproliferative effects of astaxanthin during the initiation stages of 1,2-dimethyl hydrazine-induced experimental colon carcinogenesis. Fundam Clin Pharmacol. 2009; 23(2):225-34. DOI: 10.1111/j.1472-8206.2009.00669.x. View

18.

Bournazou E, Bromberg J . Targeting the tumor microenvironment: JAK-STAT3 signaling. JAKSTAT. 2013; 2(2):e23828. PMC: 3710325. DOI: 10.4161/jkst.23828. View

19.

Yan S, Li Z, Thiele C . Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in Neuroblastoma and Pediatric Sarcomas In vitro and In vivo. Oncotarget. 2013; 4(3):433-45. PMC: 3717306. DOI: 10.18632/oncotarget.930. View

20.

Tanaka T, Shnimizu M, Moriwaki H . Cancer chemoprevention by carotenoids. Molecules. 2012; 17(3):3202-42. PMC: 6268471. DOI: 10.3390/molecules17033202. View