MH, KK and EI analyzed the date. that FF/CAP18 treatment induced increases in the expression of three miRNAs (miR-584-5p, miR-1202 and miR-3162-5p) in both HCT116 cells and exosomes. These results suggest that FF/CAP18 treatment increases exosome formation, and that exosome-encapsulated miRNAs suppress HCT116 cell proliferation. Exosomal miRNAs are considered to be involved in the dissemination of cell signals to control local cellular microenvironments. The present findings suggest that FF/CAP18 regulates cancer growth by modulating cell-to-cell communication. AMPs localize in the cytoplasm of cancer cells and enhance the expression of growth-suppressing miRNAs. These miRNAs are also transported to other cancer cells via exosomes. Therefore, transportation of these miRNAs has the potential to suppress cancer growth. AMPs exert their effects directly by targeting cancer cells and indirectly via exosomes. reported that cathelicidin LL-37 exhibits membrane-disrupting antimicrobial activity and two distinct interaction pathways: Pore formation in bilayers of unsaturated phospholipids, and membrane modulation with saturated phospholipids (28). In the present study, membrane disruption was not observed in HCT116 cells following treatment with FF/CAP18. FF/CAP18 was detected on the membrane of HCT116 cells Erastin 1 h after treatment and in the cytoplasm of the cells 6 h after treatment. These results suggest that, in cancer cells, FF/CAP18 exerted its effects without disrupting the membrane. Additionally, FF/CAP18 treatment of HCT116 cells caused the cells to secrete more exosomes than in the absence of treatment. The secretion of exosomes is regulated by cellular factors, such as intracellular calcium levels, and extracellular factors, such as chemical treatment (29,30). The enhanced exosomal export may be a stress response of HCT116 cells to FF/CAP18. The exosomes released by HCT116 cells during exposure to FF/CAP18 suppressed the viability of HCT116 cells (Fig. 3). This result indicates that exosomes released in the presence of FF/CAP18 contain a tumor suppression factor, such as miR-584-5p, miR-1202 and miR-3162-5p. The contents of protein and nucleic acids, including miRNAs, of exosomes were previously determined (13,14). miRNAs are crucial for cancer regulation (18,19). FF/CAP18 treatment changed the expression levels of miRNAs in exosomes released by HCT116 cells (Table I). FF/CAP18 treatment induced an increase of 2-fold or more in the expression of three miRNAs (miR-584-5p, miR-1202 and miR-3162-5p) in both HCT116 cells and exosomes, among which miR-584-5p and miR-1202 reportedly act as cancer suppressors. miR-584-5p was reported to inhibit proliferation and induce apoptosis of colon and gastric cancer cells (31,32). miR-584-5p induces apoptotic death by inhibiting the interaction between hnRNP A1 and CDK6 mRNA (32). miR-1202 is downregulated in ovarian cancer and clear cell papillary renal cell carcinoma (33,34). Additionally, miR-1202 suppresses glioma cell proliferation and induces apoptosis by targeting and inhibiting Rab1A (35). miR-584-5p and miR-1202 may suppress the proliferation of HCT116 cells via exosomes. By contrast, miR-3162-5p may be a new regulatory factor in colon cancer. Our group reported that AMPs upregulate the expression of miR-663a in HCT116 cells, and that this miRNA regulates the proliferation of colon cancer HCT116 cells via Erastin GRK4 the CXCR4-p21 pathway (12). However, the expression of miR-663a in exosomes was upregulated by <2-fold following FF/CAP18 treatment. Therefore, these three miRNAs may exert anticancer effects via exosomes to a greater extent compared with miR-663a. More studies are required to elucidate the mechanism by which these three miRNAs suppress cancer in order to support the use of AMPs as anti-cancer agents. The present study focused on the role of FF/CAP18. LL-37 may act in regulating cancer via exosomes. The results of this study indicate that exosomes released by cancer cells in the presence of AMPs suppress tumor growth. Several studies have suggested that exosomes secreted by cancer cells assist in cancer growth and angiogenesis, leading to cancer metastasis (15,36). By contrast, specific exosomes were found to suppress cancer growth. The secretion of miRNAs was mediated through exosomes and their quality and quantity were altered after treatment with FF/CAP18. Alterations in the miRNAs in exosomes released by cells may suppress cancer. Additionally, LL-37 and FF/CAP18, the analog of the LL-37 Erastin peptide, were previously described as anticancer agents (7,10,11). In the present study, FF/CAP18 was also found to inhibit cancer growth through exosomes. Therefore, AMPs act directly on target cancer cells and indirectly via exosomes..