Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Abstract

LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. Mechanistically, LL-37-induced activation of membrane receptors and subsequent signaling pathways lead to alteration of cellular functions. Different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37. Meanwhile, the findings that vitamin D-dependent induction of cathelicidin in human macrophages activates the anti-cancer activity of tumor-associated macrophages (TAMs) and enhances antibody-dependent cellular cytotoxicity (ADCC) support critical roles of vitamin D-dependent induction of cathelicidin in cancer progression. This review describes novel advances involving the roles and mechanisms of human cathelicidin LL-37 in cancer.

Disorder-to-helix conformational conversion of the human immunomodulatory peptide LL-37 induced by antiinflammatory drugs, food dyes and some metabolites

“…Being ubiquitously produced by epithelial cells and phagocytic leukocytes, it can be detected in a variety of tissues and body fluids such as skin, airway surfaces, gastrointestinal/urogenital tract, bone marrow, blood plasma, breast milk, saliva and tear [3,4]. In addition, the overexpression of LL-37 in some malignant tumors has recently been demonstrated [5]. Besides its broad antimicrobial activities against bacteria, fungi, and viral pathogens [6,7], LL-37 also exhibits multiple pathophysiological roles including cell proliferation, apoptosis, angiogenesis, tissue repair, chemoattraction, and even carcinogenesis/metastasis [4,8].…”

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

“…a previous study also indicated that human caMP/ll-37 was expressed at low levels in oScc, where it may exert an inhibitory effect on development, and dna methylation may serve a role in oScc by directly downregulating caMP gene promoter activity (24). Human caMP/ll-37 has multiple roles and mechanisms in various cancer cells (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)36). Both tumorigenic and anti-cancer effects induced by caMP/ll-37 have been reported in various types of cancer, and the combined effects of those involved mechanisms determine the final effect (6,9).…”

“…Human caMP/ll-37 has multiple roles and mechanisms in various cancer cells (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)36). Both tumorigenic and anti-cancer effects induced by caMP/ll-37 have been reported in various types of cancer, and the combined effects of those involved mechanisms determine the final effect (6,9). The possible mechanisms of human caMP/ll-37 in the different oScc cells have also been explored previously (22,23).…”

“…Human cathelicidin antimicrobial peptide (caMP) and its active product, ll-37, serve important roles in infectious diseases (including viral, bacterial and fungal infections) and autoimmune diseases (1)(2)(3)(4)(5). Previously, it has been found that caMP/ll-37 also has a significant effect on the initiation and progression of various types of cancer (6)(7)(8)(9). additionally, it has been indicated that the upregulation of caMP/ll-37 expression contributes to its tumorigenic effect in breast cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, malignant melanoma and skin squamous cell carcinoma (10)(11)(12)(13)(14)(15)(16).…”

“…Moreover, the downregulation of caMP/ll-37 expression contributes to its anticancer effects on colon cancer, gastric cancer and haematological malignancies (17-21). The ll-37-induced activation of membrane receptors and subsequent signalling pathways leads to the alteration of cellular functions (6)(7)(8)(9). different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37 (6)(7)(8)(9).…”