Human cathelicidin antimicrobial peptide suppresses proliferation, migration and invasion of oral carcinoma HSC-3 cells via a novel mechanism involving caspase-3 mediated apoptosis

Chen,Xi; Ji,Shenying; Si,Jia; Zhang,Xiangyu; Wang,Xiaoyan; Guo,Yong; Zou,Xianqiong

doi:10.3892/mmr.2020.11629

Human cathelicidin antimicrobial peptide suppresses proliferation, migration and invasion of oral carcinoma HSC-3 cells via a novel mechanism involving caspase-3 mediated apoptosis

Authors:
- Xi Chen
- Shenying Ji
- Jia Si
- Xiangyu Zhang
- Xiaoyan Wang
- Yong Guo
- Xianqiong Zou
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Affiliations: Laboratory of Mucosal Immunology, Affiliated Stomatology Hospital of Guilin Medical University, Guilin, Guangxi 541004, P.R. China, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
Published online on: October 23, 2020 https://doi.org/10.3892/mmr.2020.11629
Pages: 5243-5250
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Human cathelicidin antimicrobial peptide and its active product, LL‑37 (CAMP/LL‑37), exhibit a broad spectrum of antimicrobial effects. An increasing number of studies have shown that human CAMP/LL‑37 also serves significant roles in various types of cancer. The primary aims of the present study were to investigate the roles and mechanisms of human CAMP/LL‑37 in oral squamous cell carcinoma (OSCC) cells. The results indicated that either LL‑37 C‑terminal deletion mutants (CDEL) or CAMP stable expression in HSC‑3 cells reduced colony formation, proliferation, migration and invasion ability of the cells. Expression analysis demonstrated that either CDEL or CAMP stable expression in HSC‑3 cells induced caspase‑3 mediated apoptosis via the P53‑Bcl‑2/BAX signalling pathway, whereas the levels of cell cycle‑related proteins, cyclin B1 and PKR‑like ER kinase, were significantly upregulated in the CAMP, but not in the CDEL overexpressing cells. Transcriptional profile comparisons revealed that CDEL or CAMP stable expression in HSC‑3 cells upregulated expression of genes involved in the IL‑17‑dependent pathway compared with the control. Taken together, these results suggest that CAMP may act as a tumour suppressor in OSCC cells, and the underlying mechanism involves the induction of caspase‑3 mediated apoptosis via the P53‑Bcl‑2/BAX signalling pathway.

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1	Alagarasu K, Patil PS, Shil P, Seervi M, Kakade MB, Tillu H and Salunke A: In-vitro effect of human cathelicidin antimicrobial peptide LL-37 on dengue virus type 2. Peptides. 92:23–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Majewski K, Żelechowska P and Brzezińska-Błaszczyk E: Circulating cathelicidin LL-37 in adult patients with pulmonary infectious diseases. Clin Invest Med. 40:E34–E39. 2017. View Article : Google Scholar : PubMed/NCBI
3	Tsai PW, Yang CY, Chang HT and Lan CY: Human antimicrobial peptide LL-37 inhibits adhesion of Candida albicans by interacting with yeast cell-wall carbohydrates. PLoS One. 6:e177552011. View Article : Google Scholar : PubMed/NCBI
4	Polcyn-Adamczak M and Niemir ZI: Cathelicidin - Its structure, function and the role in autoimmune diseases. Adv Cell Biol. 4:83–96. 2014. View Article : Google Scholar
5	Kahlenberg JM and Kaplan MJ: Little peptide, big effects: The role of LL-37 in inflammation and autoimmune disease. J Immunol. 191:4895–4901. 2013. View Article : Google Scholar : PubMed/NCBI
6	Piktel E, Niemirowicz K, Wnorowska U, Wątek M, Wollny T, Głuszek K, Góźdź S, Levental I and Bucki R: The role of cathelicidin LL-37 in cancer development. Arch Immunol Ther Exp (Warsz). 64:33–46. 2016. View Article : Google Scholar : PubMed/NCBI
7	Wu WK, Wang G, Coffelt SB, Betancourt AM, Lee CW, Fan D, Wu K, Yu J, Sung JJ and Cho CH: 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
8	Kuroda K, Okumura K, Isogai H and Isogai E: The human cathelicidin antimicrobial peptide LL-37 and mimics are potential anticancer drugs. Front Oncol. 5:1442015. View Article : Google Scholar : PubMed/NCBI
9	Chen X, Zou X, Qi G, Tang Y, Guo Y, Si J and Liang L: Roles and mechanism of human cathelicidin LL-37 in cancer. Cell Physiol Biochem. 47:1060–1073. 2018. View Article : Google Scholar : PubMed/NCBI
10	Carmona FJ, Montemurro F, Kannan S, Rossi V, Verma C, Baselga J and Scaltriti M: AKT signaling in ERBB2-amplified breast cancer. Pharmacol Ther. 158:63–70. 2016. View Article : Google Scholar : PubMed/NCBI
11	Li D, Wang X, Wu JL, Quan WQ, Ma L, Yang F, Wu KY and Wan HY: Tumor-produced versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and vitamin D3 signaling to promote ovarian cancer progression in vitro. PLoS One. 8:e566162013. View Article : Google Scholar : PubMed/NCBI
12	von Haussen J, Koczulla R, Shaykhiev R, Herr C, Pinkenburg O, Reimer D, Wiewrodt R, Biesterfeld S, Aigner A, Czubayko F, et al: The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer. 59:12–23. 2008. View Article : Google Scholar : PubMed/NCBI
13	Hensel JA, Chanda D, Kumar S, Sawant A, Grizzle WE, Siegal GP and Ponnazhagan S: LL-37 as a therapeutic target for late stage prostate cancer. Prostate. 71:659–670. 2011. View Article : Google Scholar : PubMed/NCBI
14	Sainz B Jr, Alcala S, Garcia E, Sanchez-Ripoll Y, Azevedo MM, Cioffi M, Tatari M, Miranda-Lorenzo I, Hidalgo M, Gomez-Lopez G, et al: Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut. 64:1921–1935. 2015. View Article : Google Scholar : PubMed/NCBI
15	Muñoz M, Craske M, Severino P, de Lima TM, Labhart P, Chammas R, Velasco IT, Machado MC, Egan B, Nakaya HI, et al: Antimicrobial peptide LL-37 participates in the transcriptional regulation of melanoma cells. J Cancer. 7:2341–2345. 2016. View Article : Google Scholar : PubMed/NCBI
16	Wang W, Zheng Y, Jia J, Li C, Duan Q, Li R, Wang X, Shao Y, Chen C and Yan H: Antimicrobial peptide LL-37 promotes the viability and invasion of skin squamous cell carcinoma by upregulating YB-1. Exp Ther Med. 14:499–506. 2017. View Article : Google Scholar : PubMed/NCBI
17	17. Wu WK, Sung JJ, To KF, Yu L, Li HT, Li ZJ, Chu KM, Yu J and Cho CH: The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells. J Cell Physiol. 223:178–186. 2010.PubMed/NCBI
18	Ren SX, Cheng AS, To KF, Tong JH, Li MS, Shen J, Wong CC, Zhang L, Chan RL, Wang XJ, 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
19	Kuroda K, Fukuda T, Krstic-Demonacos M, Demonacos C, Okumura K, Isogai H, Hayashi M, Saito K and Isogai E: miR-663a regulates growth of colon cancer cells, after administration of antimicrobial peptides, by targeting CXCR4-p21 pathway. BMC Cancer. 17:332017. View Article : Google Scholar : PubMed/NCBI
20	Mader JS, Mookherjee N, Hancock RE and Bleackley RC: The human host defense peptide LL-37 induces apoptosis in a calpain- and apoptosis-inducing factor-dependent manner involving Bax activity. Mol Cancer Res. 7:689–702. 2009. View Article : Google Scholar : PubMed/NCBI
21	An LL, Ma XT, Yang YH, Lin YM, Song YH and Wu KF: Marked reduction of LL-37/hCAP-18, an antimicrobial peptide, in patients with acute myeloid leukemia. Int J Hematol. 81:45–47. 2005. View Article : Google Scholar : PubMed/NCBI
22	Okumura K, Itoh A, Isogai E, Hirose K, Hosokawa Y, Abiko Y, Shibata T, Hirata M and Isogai H: C-terminal domain of human CAP18 antimicrobial peptide induces apoptosis in oral squamous cell carcinoma SAS-H1 cells. Cancer Lett. 212:185–194. 2004.PubMed/NCBI
23	Açil Y, Torz K, Gülses A, Wieker H, Gerle M, Purcz N, Will OM, Eduard Meyer J and Wiltfang J: An experimental study on antitumoral effects of KI-21-3, a synthetic fragment of antimicrobial peptide LL-37, on oral squamous cell carcinoma. J Craniomaxillofac Surg. 46:1586–1592. 2018.PubMed/NCBI
24	Chen X, Qi G, Qin M, Zou Y, Zhong K, Tang Y, Guo Y, Jiang X, Liang L and Zou X: DNA methylation directly downregulates human cathelicidin antimicrobial peptide gene (CAMP) promoter activity. Oncotarget. 8:27943–27952. 2017.PubMed/NCBI
25	Väyrynen O, Åström P, Nyberg P, Alahuhta I, Pirilä E, Vilen ST, Aikio M, Heljasvaara R, Risteli M, Sutinen M, et al: Matrix metalloproteinase 9 inhibits the motility of highly aggressive HSC-3 oral squamous cell carcinoma cells. Exp Cell Res. 376:18–26. 2019.PubMed/NCBI
26	Chang WL, Cheng FC, Wang SP, Chou ST and Shih Y: Cinnamomum cassia essential oil and its major constituent cinnamaldehyde induced cell cycle arrest and apoptosis in human oral squamous cell carcinoma HSC-3 cells. Environ Toxicol. 32:456–468. 2017.PubMed/NCBI
27	Araújo T, Khayat A, Quintana L, Calcagno D, Mourão R, Modesto A, Paiva J, Lima A, Moreira F, Oliveira E, et al: Piwi like RNA-mediated gene silencing 1 gene as a possible major player in gastric cancer. World J Gastroenterol. 24:5338–5350. 2018.PubMed/NCBI
28	Tang B, Qi G, Tang F, Yuan S, Wang Z, Liang X, Li B, Yu S, Liu J, Huang Q, et al: Aberrant JMJD3 expression upregulates slug to promote migration, invasion, and stem cell-like behaviors in hepatocellular carcinoma. Cancer Res. 76:6520–6532. 2016.PubMed/NCBI
29	Qi G, Kudo Y, Tang B, Liu T, Jin S, Liu J, Zuo X, Mi S, Shao W, Ma X, et al: PARP6 acts as a tumor suppressor via downregulating Survivin expression in colorectal cancer. Oncotarget. 7:18812–18824. 2016.PubMed/NCBI
30	Zhao JG, Wang JF, Feng JF, Jin XY and Ye WL: HHIP overexpression inhibits the proliferation, migration and invasion of non-small cell lung cancer. PLoS One. 14:e02257552019.PubMed/NCBI
31	Duan Q, Xiao Y, Zhu L, Liu Z, Mao X, Zhou Z, Liao C, Cai J, Huang F, Liu Z, et al: BET bromodomain is a novel regulator of TAZ and its activity. Biochim Biophys Acta. 1859:1527–1537. 2016.PubMed/NCBI
32	Mortazavi A, Williams BA, McCue K, Schaeffer L and Wold B: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 5:621–628. 2008.PubMed/NCBI
33	Anders S and Huber W: Differential expression analysis for sequence count data. Genome Biol. 11:R1062010.PubMed/NCBI
34	Vonderheide RH: Tumor-promoting inflammatory networks in pancreatic neoplasia: Another reason to loathe Kras. Cancer Cell. 25:553–554. 2014.PubMed/NCBI
35	Kim YK, Shin JS and Nahm MH: NOD-like receptors in infection, immunity, and diseases. Yonsei Med J. 57:5–14. 2016.PubMed/NCBI
36	Tuomela JM, Sandholm JA, Kaakinen M, Hayden KL, Haapasaari KM, Jukkola-Vuorinen A, Kauppila JH, Lehenkari PP, Harris KW, Graves DE, et al: Telomeric G-quadruplex-forming DNA fragments induce TLR9-mediated and LL-37-regulated invasion in breast cancer cells in vitro. Breast Cancer Res Treat. 155:261–271. 2016.PubMed/NCBI
37	Cheng M, Ho S, Yoo JH, Tran DH, Bakirtzi K, Su B, Tran DH, Kubota Y, Ichikawa R and Koon HW: Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts. Clin Exp Gastroenterol. 8:13–29. 2014.PubMed/NCBI
38	Martini M, De Santis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signaling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014.PubMed/NCBI
39	Sun Y, Liu WZ, Liu T, Feng X, Yang N and Zhou HF: Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res. 35:600–604. 2015.PubMed/NCBI