Antimicrobial peptide FF/CAP18 induces apoptotic cell death in HCT116 colon cancer cells via changes in the metabolic profile

Kuroda,Kengo; Fukuda,Tomokazu; Isogai,Hiroshi; Okumura,Kazuhiko; Krstic-Demonacos,Marija; Isogai,Emiko

doi:10.3892/ijo.2015.2887

Antimicrobial peptide FF/CAP18 induces apoptotic cell death in HCT116 colon cancer cells via changes in the metabolic profile

Authors:
- Kengo Kuroda
- Tomokazu Fukuda
- Hiroshi Isogai
- Kazuhiko Okumura
- Marija Krstic-Demonacos
- Emiko Isogai
View Affiliations

Affiliations: Graduate School of Agricultural Science, Tohoku University, Aoba-ku, Sendai 981-8555, Japan, Animal Research Center, Sapporo Medical University, Sapporo 060-8556, Japan, Department of Oral and Maxillofacial Surgery, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido 061-0293, Japan, School of Environment and Life Sciences, College of Science and Technology, Cockcroft Building, University of Salford, Salford M5 4WT, UK
Published online on: February 10, 2015 https://doi.org/10.3892/ijo.2015.2887
Pages: 1516-1526
Copyright: © Kuroda et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Metabolic reprogramming is one of the hallmarks of cancer and can be targeted by therapeutic agents. We previously reported that cathelicidin-related or modified antimicrobial peptides, such as FF/CAP18, have antiproliferative effects on the squamous cell carcinoma cell line SAS-H1, and the colon carcinoma cell line HCT116. Although antimicrobial peptides have potential use in the development of new therapeutic strategies, their effects on the metabolism of cancer cells are poorly understood. Here, we investigated changes in the levels of metabolites in HCT116 cells caused by FF/CAP18, via capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Analysis of the 177 intracellular metabolites and 113 metabolites in conditioned medium that were detected by CE-TOFMS, revealed dramatic changes in the metabolic profile of HCT116 cells after treatment with FF/CAP18. The metabolic profile showed that the levels of most metabolites in the major metabolic pathways supported the rapid proliferation of cancer cells. Purine metabolism, glycolysis, and the TCA cycle, were altered in FF/CAP18-treated cells in a dose-dependent manner. Our present study provides mechanistic insights into the anticancer effects of antimicrobial peptides that show great potential as new therapies for colon cancer.

View Figures

View References

1	The global burden of disease: 2004 update. WHO Library Cataloguing-in-Publication Data. 2008, http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/.
2	Cancer statistics: Worldwide. World Cancer Research Fund International Web site. http://www.wcrf.org/int/cancer-facts-figures/worldwide-data.
3	Cairns RA, Harris IS and Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 11:85–95. 2011. View Article : Google Scholar : PubMed/NCBI
4	Phan LM, Yeung SC and Lee MH: Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med. 11:1–19. 2014.PubMed/NCBI
5	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
6	Hirayama A, Kami K, Sugimoto M, et al: Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 69:4918–4925. 2009. View Article : Google Scholar : PubMed/NCBI
7	Soga T, Baran R, Suematsu M, et al: Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem. 281:16768–16776. 2006. View Article : Google Scholar : PubMed/NCBI
8	Saito K: Phytochemical genomics - a new trend. Curr Opin Plant Biol. 16:373–380. 2013. View Article : Google Scholar : PubMed/NCBI
9	Mashego MR, Rumbold K, De Mey M, Vandamme E, Soetaert W and Heijnen JJ: Microbial metabolomics: past, present and future methodologies. Biotechnol Lett. 29:1–16. 2007. View Article : Google Scholar
10	Spratlin JL, Serkova NJ and Eckhardt SG: Clinical applications of metabolomics in oncology: a review. Clin Cancer Res. 15:431–440. 2009. View Article : Google Scholar : PubMed/NCBI
11	Oliver S: Guilt-by-association goes global. Nature. 403:601–603. 2000. View Article : Google Scholar : PubMed/NCBI
12	Fiehn O: Metabolomics - the link between genotypes and phenotypes. Plant Mol Biol. 48:155–171. 2002. View Article : Google Scholar : PubMed/NCBI
13	Wu WK, Wang G, Coffelt SB, et al: Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. Int J Cancer. 127:1741–1747. 2010. View Article : Google Scholar : PubMed/NCBI
14	Zaiou M and Gallo RL: Cathelicidins, essential gene-encoded mammalian antibiotics. J Mol Med (Berl). 80:549–561. 2002. View Article : Google Scholar
15	Zanetti M: The role of cathelicidins in the innate host defenses of mammals. Curr Issues Mol Biol. 7:179–196. 2005.PubMed/NCBI
16	Bals R, Wang X, Zasloff M and Wilson JM: The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci USA. 95:9541–9546. 1998. View Article : Google Scholar : PubMed/NCBI
17	Ren SX, Cheng AS, To KF, et al: Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res. 72:6512–6523. 2012. View Article : Google Scholar : PubMed/NCBI
18	Okumura K, Itoh A, Isogai E, et al: C-terminal domain of human CAP18 antimicrobial peptide induces apoptosis in oral squamous cell carcinoma SAS-H1 cells. Cancer Lett. 212:185–194. 2004. View Article : Google Scholar : PubMed/NCBI
19	Kuroda K, Fukuda T, Yoneyama H, et al: Anti-proliferative effect of an analogue of the LL-37 peptide in the colon cancer derived cell line HCT116 p53^+/+ and p53. Oncol Rep. 28:829–834. 2012.PubMed/NCBI
20	Isogai E, Isogai H, Matuo K, et al: Sensitivity of genera Porphyromonas and Prevotella to the bactericidal action of C-terminal domain of human CAP18 and its analogues. Oral Microbiol Immunol. 18:329–332. 2003. View Article : Google Scholar : PubMed/NCBI
21	Soga T and Heiger DN: Amino acid analysis by capillary electrophoresis electrospray ionization mass spectrometry. Anal Chem. 72:1236–1241. 2000. View Article : Google Scholar : PubMed/NCBI
22	Soga T, Ueno Y, Naraoka H, Ohashi Y, Tomita M and Nishioka T: Simultaneous determination of anionic intermediates for Bacillus subtilis metabolic pathways by capillary electrophoresis electrospray ionization mass spectrometry. Anal Chem. 74:2233–2239. 2002. View Article : Google Scholar : PubMed/NCBI
23	Soga T, Ohashi Y, Ueno Y, Naraoka H, Tomita M and Nishioka T: Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J Proteome Res. 2:488–494. 2003. View Article : Google Scholar : PubMed/NCBI
24	Sugimoto M, Wong DT, Hirayama A, Soga T and Tomita M: Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics. 6:78–95. 2010. View Article : Google Scholar : PubMed/NCBI
25	Junker BH, Klukas C and Schreiber F: VANTED: a system for advanced data analysis and visualization in the context of biological networks. BMC Bioinformatics. 7:1092006. View Article : Google Scholar : PubMed/NCBI
26	Gaspar D, Veiga AS and Castanho MA: From antimicrobial to anticancer peptides. A review. Front Microbiol. 4:2942013. View Article : Google Scholar : PubMed/NCBI
27	Wu D, Gao Y, Qi Y, Chen L, Ma Y and Li Y: Peptide-based cancer therapy: opportunity and challenge. Cancer Lett. 351:13–22. 2014. View Article : Google Scholar : PubMed/NCBI
28	Bensaad K, Tsuruta A, Selak MA, et al: TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 126:107–120. 2006. View Article : Google Scholar : PubMed/NCBI
29	Hu Y, Benedict MA, Ding L and Nunez G: Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 18:3586–3595. 1999. View Article : Google Scholar : PubMed/NCBI
30	Li P, Nijhawan D, Budihardjo I, et al: Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 91:479–489. 1997. View Article : Google Scholar : PubMed/NCBI
31	Kass GE, Eriksson JE, Weis M, Orrenius S and Chow SC: Chromatin condensation during apoptosis requires ATP. Biochem J. 318:749–752. 1996.PubMed/NCBI
32	Barros LF, Kanaseki T, Sabirov R, et al: Apoptotic and necrotic blebs in epithelial cells display similar neck diameters but different kinase dependency. Cell Death Differ. 10:687–697. 2003. View Article : Google Scholar : PubMed/NCBI
33	Leist M, Single B, Castoldi AF, Kuhnle S and Nicotera P: Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med. 185:1481–1486. 1997. View Article : Google Scholar : PubMed/NCBI
34	Zamaraeva MV, Sabirov RZ, Maeno E, Ando-Akatsuka Y, Bessonova SV and Okada Y: Cells die with increased cytosolic ATP during apoptosis: a bioluminescence study with intracel-lular luciferase. Cell Death Differ. 12:1390–1397. 2005. View Article : Google Scholar : PubMed/NCBI
35	Center MM, Jemal A, Smith RA and Ward E: Worldwide variations in colorectal cancer. CA Cancer J Clin. 59:366–378. 2009. View Article : Google Scholar : PubMed/NCBI
36	Gentilucci L, Tolomelli A and Squassabia F: Peptides and pepti-domimetics in medicine, surgery and biotechnology. Curr Med Chem. 13:2449–2466. 2006. View Article : Google Scholar
37	Hancock RE and Diamond G: The role of cationic antimicrobial peptides in innate host defences. Trends Microbiol. 8:402–410. 2000. View Article : Google Scholar : PubMed/NCBI
38	Ren SX, Shen J, Cheng AS, et al: FK-16 derived from the anti-cancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells. PLoS One. 8:e636412013. View Article : Google Scholar