Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Regulatory role of Echinochrome A in cancer-associated fibroblast-mediated lung cancer cell migration

  • Da‑Young Eum (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Chaeyoung Lee (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Cong So Tran (College of Pharmacy and Research Institute for Drug Development, Pusan National University) ;
  • Jinyoung Lee (College of Pharmacy and Research Institute for Drug Development, Pusan National University) ;
  • Soon Yong Park (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Mi‑So Jeong (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Yunho Jin (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Jae Woong Shim (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Seoung Rak Lee (College of Pharmacy and Research Institute for Drug Development, Pusan National University) ;
  • Minseob Koh (Department of Chemistry, Pusan National University) ;
  • Elena A. Vasileva (G.B. Elyakov Pacifc Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Science) ;
  • Natalia P. Mishchenko (G.B. Elyakov Pacifc Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Science) ;
  • Seong‑Joon Park (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Si Ho Choi (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Yoo Jin Choi (Research Center, Dongnam Institute of Radiological & Medical Sciences) ;
  • Hwayoung Yun (College of Pharmacy and Research Institute for Drug Development, Pusan National University) ;
  • Kyu Heo (Research Center, Dongnam Institute of Radiological & Medical Sciences)
  • Received : 2024.01.08
  • Accepted : 2024.03.13
  • Published : 2024.07.15
⟨ Previous Next ⟩

Abstract

Echinochrome A (Ech A), a marine biosubstance isolated from sea urchins, is a strong antioxidant, and its clinical form, histochrome, is being used to treat several diseases, such as ophthalmic, cardiovascular, and metabolic diseases. Cancer-associated fibroblasts (CAFs) are a component of the tumor stroma and induce phenotypes related to tumor malignancy, including epithelial-mesenchymal transition (EMT) and cancer stemness, through reciprocal interactions with cancer cells. Here, we investigated whether Ech A modulates the properties of CAFs and alleviates CAF-induced lung cancer cell migration. First, we observed that the expression levels of CAF markers, Vimentin and fibroblast-activating protein (FAP), were decreased in Ech A-treated CAF-like MRC5 cells. The mRNA transcriptome analysis revealed that in MRC5 cells, the expression of genes associated with cell migration was largely modulated after Ech A treatment. In particular, the expression and secretion of cytokine and chemokine, such as IL6 and CCL2, stimulating cancer cell metastasis was reduced through the inactivation of STAT3 and Akt in MRC5 cells treated with Ech A compared to untreated MRC5 cells. Moreover, while conditioned medium from MRC5 cells enhanced the migration of non-small cell lung cancer cells, conditioned medium from MRC5 cells treated with Ech A suppressed cancer cell migration. In conclusion, we suggest that Ech A might be a potent adjuvant that increases the efficacy of cancer treatments to mitigate lung cancer progression.

Keywords

Acknowledgement

This work was supported by the a Dongnam Institute of Radiological & Medical Sciences (DIRAMS) grant funded by the Korean government (MSIT) (50591-2023), a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2021R1A2C1095736) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2023R1A2C1007018).

References

  1. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7-30. https://doi.org/10.3322/caac.21442
  2. Altorki NK, Markowitz GJ, Gao D, Port JL, Saxena A, Stiles B, McGraw T, Mittal V (2019) The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer 19:9-31. https://doi.org/10.1038/s41568-018-0081-9
  3. Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871-890. https://doi.org/10.1016/j.cell.2009.11.007
  4. Neophytou CM, Panagi M, Stylianopoulos T, Papageorgis P (2021) The role of tumor microenvironment in cancer metastasis: molecular mechanisms and therapeutic opportunities. Cancers 13:2053. https://doi.org/10.3390/cancers13092053
  5. Giraldo NA, Sanchez-Salas R, Peske JD, Vano Y, Becht E, Petitprez F, Validire P, Ingels A, Cathelineau X, Fridman WH, Sautes-Fridman C (2019) The clinical role of the TME in solid cancer. Br J Cancer 120:45-53. https://doi.org/10.1038/s41416-018-0327-z
  6. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C (2001) Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 10:1907-1913. https://doi.org/10.1093/hmg/10.18.1907
  7. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59:5002-5011. https://doi.org/10.1186/bcr138
  8. Bhome R, Goh RW, Bullock MD et al (2017) Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression. Aging 9:2666-2694. https://doi.org/10.18632/aging.101355
  9. Bhome R, Goh R, Pickard K, Mellone M, Sayan AE, Mirnezami A (2017) Profiling the microRNA payload of exosomes derived from ex vivo primary colorectal fibroblasts. Methods Mol Biol 1509:115-122. https://doi.org/10.1007/978-1-4939-6524-3_11
  10. Luga V, Zhang L, Viloria-Petit Alicia M, Ogunjimi Abiodun A, Inanlou Mohammad R, Chiu E, Buchanan M, Hosein Abdel N, Basik M, Wrana Jeffrey L (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542-1556. https://doi.org/10.1016/j.cell.2012.11.024
  11. Erdogan B, Webb DJ (2017) Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans 45:229-236. https://doi.org/10.1042/BST20160387
  12. Sahai E, Astsaturov I, Cukierman E et al (2020) A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 20:174-186. https://doi.org/10.1038/s41568-019-0238-1
  13. Han C, Liu T, Yin R (2020) Biomarkers for cancer-associated fibroblasts. Biomark Res 8:64. https://doi.org/10.1186/s40364-020-00245-w
  14. Cheng SH, Chiou HYC, Wang JW, Lin MH (2023) Reciprocal regulation of cancer-associated fibroblasts and tumor microenvironment in gastrointestinal cancer: implications for cancer dormancy. Cancers 15:2513. https://doi.org/10.3390/cancers15092513
  15. Anderson HA, Mathieson JW, Thomson RH (1969) Distribution of spinochrome pigments in echinoids. Comp Biochem Physiol 28:333-345. https://doi.org/10.1016/0010-406x(69)91347-4
  16. Vasileva EA, Mishchenko NP, Tran VTT, Vo HMN, Bui LM, Denisenko VA, Fedoreyev SA (2017) Quinoid pigments from the sea urchin Astropyga radiata. Chem Nat Compd 53:356-358. https://doi.org/10.1007/s10600-017-1988-1
  17. Gerasimenko AV, Fedoreyev SA, Mischenko NP (2006) Molecular and crystal structure of the echinochrome complex with dioxane. Crystallogr Rep 51:42-46. https://doi.org/10.1134/s1063774506010093
  18. Kim R, Hur D, Kim HK, Han J, Mishchenko NP, Fedoreyev SA, Stonik VA, Chang W (2019) Echinochrome A attenuates cerebral ischemic injury through regulation of cell survival after middle cerebral artery occlusion in rat. Mar Drugs 17:501. https://doi.org/10.3390/md17090501
  19. Afanas'ev SA, Lasukova TV, Chernyavskii AM (1997) ATP-sparing effect of histochrome in acute myocardial ischemia in patients with coronary heart disease. Bull Exp Biol Med 124:1217-1219. https://doi.org/10.1007/bf02445124
  20. Park GT, Yoon JW, Yoo SB et al (2021) Echinochrome A treatment alleviates fibrosis and inflammation in bleomycin-induced scleroderma. Mar Drugs 19:237. https://doi.org/10.3390/md19050237
  21. Choi MR, Lee H, Kim HK, Han J, Seol JE, Vasileva EA, Mishchenko NP, Fedoreyev SA, Stonik VA, Ju WS, Kim D-J, Lee S-R (2022) Echinochrome A inhibits melanogenesis in B16F10 cells by downregulating CREB signaling. Mar Drugs 20:555. https://doi.org/10.3390/md20090555
  22. Sadek SA, Hassanein SS, Mohamed AS, Soliman AM, Fahmy SR (2022) Echinochrome pigment extracted from sea urchin suppress the bacterial activity, inflammation, nociception, and oxidative stress resulted in the inhibition of renal injury in septic rats. J Food Biochem 46:e13729. https://doi.org/10.1111/jfbc.13729
  23. Fedoreyev SA, Krylova NV, Mishchenko NP, Vasileva EA, Pislyagin EA, Iunikhina OV, Lavrov VF, Svitich OA, Ebralidze LK, Leonova GN (2018) Antiviral and antioxidant properties of echinochrome A. Mar Drugs 16:509. https://doi.org/10.3390/md16120509
  24. Rubilar T, Barbieri ES, Gazquez A, Avaro M (2021) Sea urchin pigments: echinochrome A and its potential implication in the cytokine storm syndrome. Mar Drugs 19:267. https://doi.org/10.3390/md19050267
  25. Camini FC, da Silva Caetano CC, Almeida LT, de Brito Magalhaes CL (2017) Implications of oxidative stress on viral pathogenesis. Arch Virol 162:907-917. https://doi.org/10.1007/s00705-016-3187-y
  26. Artyukov AA, Zelepuga EA, Bogdanovich LN, Lupach NM, Novikov VL, Rutckova TA, Kozlovskaya EP (2020) Marine polyhydroxynaphthoquinone, echinochrome A: prevention of atherosclerotic inflammation and probable molecular targets. J Clin Med 9:1494. https://doi.org/10.3390/jcm9051494
  27. Shikov AN, Pozharitskaya ON, Krishtopina AS, Makarov VG (2018) Naphthoquinone pigments from sea urchins: chemistry and pharmacology. Phytochem Rev 17:509-534. https://doi.org/10.1007/s11101-018-9547-3
  28. Mischenko NP, Fedoreyev SA, Pokhilo ND, Anufriev VP, Denisenko VA, Glazunov VP (2005) Echinamines A and B, first aminated hydroxynaphthazarins from the sea urchin Scaphechinus mirabilis. J Nat Prod 68:1390-1393. https://doi.org/10.1021/np049585r
  29. Kim D, Langmead B, Salzberg SL (2015) HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12:357-360. https://doi.org/10.1038/nmeth.3317
  30. Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923-930. https://doi.org/10.1093/bioinformatics/btt656
  31. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. https://doi.org/10.1186/s13059-014-0550-8
  32. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics (Oxford, England) 26:139-140. https://doi.org/10.1093/bioinformatics/btp616
  33. Chen J, Bardes EE, Aronow BJ, Jegga AG (2009) ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 37:W305-W311. https://doi.org/10.1093/nar/gkp427
  34. Ge SX, Jung D, Yao R (2020) ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics (Oxford, England) 36:2628-2629. https://doi.org/10.1093/bioinformatics/btz931
  35. Raivo K (2019) Package 'pheatmap'. Publishing CRAN Web. https://cran.r-project.org/web/packages/pheatmap/pheatmap.pdf. Accessed 4 Jan 2019
  36. Kim HK, Cho SW, Heo HJ, Jeong SH, Kim M, Ko KS, Rhee BD, Mishchenko NP, Vasileva EA, Fedoreyev SA, Stonik VA, Han J (2018) A novel atypical PKC-Iota inhibitor, echinochrome A, enhances cardiomyocyte differentiation from mouse embryonic stem cells. Mar Drugs 16:192. https://doi.org/10.3390/md16060192
  37. Ding S, Chen G, Zhang W, Xing C, Xu X, Xie H, Lu A, Chen K, Guo H, Ren Z, Zheng S, Zhou L (2015) MRC-5 fibroblast-conditioned medium influences multiple pathways regulating invasion, migration, proliferation, and apoptosis in hepatocellular carcinoma. J Transl Med 13:237. https://doi.org/10.1186/s12967-015-0588-8
  38. Wang W, Li Q, Takeuchi S et al (2012) Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Clin Cancer Res 18:1663-1671. https://doi.org/10.1158/1078-0432.ccr-11-1171
  39. Kayalar O, Oztay F, Ongen HG (2020) Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s. Cell Commun Signal 18:96. https://doi.org/10.1186/s12964-020-00585-y
  40. Heylen N, Baurain R, Remacle C, Trouet A (1998) Efect of MRC-5 fibroblast conditioned medium on breast cancer cell motility and invasion in vitro. Clin Exp Metast 16:193-203. https://doi.org/10.1023/a:1006532523152
  41. Song BW, Kim S, Kim R et al (2022) Regulation of inflammation-mediated endothelial to mesenchymal transition with echinochrome a for improving myocardial dysfunction. Mar Drugs 20:756. https://doi.org/10.3390/md20120756
  42. Lennikov A, Kitaichi N, Noda K, Mizuuchi K, Ando R, Dong Z, Fukuhara J, Kinoshita S, Namba K, Ohno S, Ishida S (2014) Amelioration of endotoxin-induced uveitis treated with the sea urchin pigment echinochrome in rats. Mol Vis 20:171-177
  43. Taniguchi K, Karin M (2018) NF-κB, infammation, immunity and cancer: coming of age. Nat Rev Immunol 18:309-324. https://doi.org/10.1038/nri.2017.142
  44. Liu T, Zhang L, Joo D, Sun S-C (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:17023. https://doi.org/10.1038/sigtrans.2017.23
  45. Yoon S, Woo SU, Kang JH, Kim K, Shin HJ, Gwak HS, Park S, Chwae YJ (2012) NF-κB and STAT3 cooperatively induce IL6 in starved cancer cells. Oncogene 31:3467-3481. https://doi.org/10.1038/onc.2011.517
  46. Grivennikov SI, Karin M (2010) Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21:11-19. https://doi.org/10.1016/j.cytogfr.2009.11.005
  47. Kalluri R, Weinberg RA (2010) The basics of epithelial-mesenchymal transition. J Clin Investig 120:1786. https://doi.org/10.1172/jci39104c1
  48. Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, Liu J, Wang Q, Zhu J, Feng X, Dong J, Qian C (2013) Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxiainducible factor -1α in hepatocellular carcinoma. BMC Cancer 13:108. https://doi.org/10.1186/1471-2407-13-108
  49. Huang Y, Hong W, Wei X (2022) The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 15:129. https://doi.org/10.1186/s13045-022-01347-8
  50. Chang JW, Seo ST, Im MA, Won H-R, Liu L, Oh C, Jin YL, Piao Y, Kim HJ, Kim JT, Jung SN, Koo BS (2022) Claudin-1 mediates progression by regulating EMT through AMPK/TGF-β signaling in head and neck squamous cell carcinoma. Transl Res 247:58-78. https://doi.org/10.1016/j.trsl.2022.04.003
  51. Suh Y, Yoon CH, Kim RK, Lim EJ, Oh YS, Hwang SG, An S, Yoon G, Gye MC, Yi JM, Kim MJ, Lee SJ (2013) Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Oncogene 32:4873-4882. https://doi.org/10.1038/onc.2012.505