C-terminal domain of human CAP18 antimicrobial peptide induces apoptosis in oral squamous cell carcinoma SAS-H1 cells.

Mammalian myeloid and epithelial cells express many antimicrobiotic peptides that contribute to innate host defense against invading microbes. In the present study, a 27-mer peptide of the C-terminal domain (hCAP18(109-135)) and analogs of the antimicrobial peptide human cathelicidin LL-37/human cationic antimicrobial protein 18 (hCAP18) were examined for tumoricidal activity. In vitro results showed that hCAP18(109-135) induced apoptosis in human oral squamous cell carcinoma (OSCC), SAS-H1 cells. The hCAP18(109-135) induced mitochondrial depolarization and apoptosis in SAS-H1 cells, but not in healthy human gingival fibroblasts (HGF) and human keratinocyte line HaCaT cells. Caspases were not activated during hCAP18(109-135)-induced apoptosis in SAS-H1 cells. The results indicate that hCAP18(109-135) may induce caspase-independent apoptosis in OSCC but not in normal cells. hCAP18(109-135) can therefore be a useful anti-tumor therapeutic agent in the treatment of OSCC.

[1]  K. Berndt,et al.  Conformation-dependent Antibacterial Activity of the Naturally Occurring Human Peptide LL-37* , 1998, The Journal of Biological Chemistry.

[2]  J. Odeberg,et al.  FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Bals,et al.  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. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Y. Ohmori,et al.  Spontaneous production of thymocyte-activating factor by human gingival fibroblasts and its autoregulatory effect on their proliferation , 1987, Infection and immunity.

[5]  H. Wigzell,et al.  The Expression of the Gene Coding for the Antibacterial Peptide LL-37 Is Induced in Human Keratinocytes during Inflammatory Disorders* , 1997, The Journal of Biological Chemistry.

[6]  V. Cryns,et al.  Proteases to die for. , 1998, Genes & development.

[7]  M. Ståhle-Bäckdahl,et al.  The Human Cationic Antimicrobial Protein (hCAP18), a Peptide Antibiotic, Is Widely Expressed in Human Squamous Epithelia and Colocalizes with Interleukin-6 , 1999, Infection and Immunity.

[8]  E. Isogai,et al.  Sensitivity of genera Porphyromonas and Prevotella to the bactericidal action of C-terminal domain of human CAP18 and its analogues. , 2003, Oral microbiology and immunology.

[9]  P. Petit,et al.  Another genotoxic agent released by mitochondrial meltdown , 2001, Cell Death and Differentiation.

[10]  W. Hanstein,et al.  Uncoupling of oxidative phosphorylation. , 1976, Biochimica et biophysica acta.

[11]  Y. Shai,et al.  Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. , 1999, The Biochemical journal.

[12]  H. Jörnvall,et al.  The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. , 2000, Blood.

[13]  J. Odeberg,et al.  The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. , 1996, European journal of biochemistry.

[14]  B. Lang,et al.  Mitochondrial evolution. , 1999, Science.

[15]  J. Hornung,et al.  Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line , 1988, The Journal of cell biology.

[16]  G. Azzone,et al.  Uncoupling of oxidative phosphorylation. 1. Protonophoric effects account only partially for uncoupling. , 1987, Biochemistry.

[17]  T. Ohtake,et al.  Cathelicidin Antimicrobial Peptides are Expressed in Salivary Glands and Saliva , 2002, Journal of dental research.

[18]  James M. Wilson,et al.  Cathelicidins - a family of multifunctional antimicrobial peptides , 2003, Cellular and Molecular Life Sciences CMLS.

[19]  G. Kroemer,et al.  Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death , 1995, The Journal of experimental medicine.

[20]  R. Gennaro,et al.  Structure and biology of cathelicidins. , 2000, Advances in experimental medicine and biology.

[21]  K. Rabe,et al.  Human neutrophil defensins induce lung epithelial cell proliferation in vitro , 2002, Journal of leukocyte biology.

[22]  Y. Lazebnik,et al.  Oncogene-dependent apoptosis is mediated by caspase-9. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Lehrer,et al.  Sensitivity of Actinobacillus actinomycetemcomitans and Capnocytophaga spp. to the bactericidal action of LL-37: a cathelicidin found in human leukocytes and epithelium. , 2000, Oral microbiology and immunology.

[24]  C. Bucana,et al.  Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. , 1991, Cancer research.

[25]  P. Vandenabeele,et al.  Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation , 2001, Cell Death and Differentiation.

[26]  Y. Niitsu,et al.  Establishment of high- and low-invasion clones derived for a human tongue squamous-cell carcinoma cell line SAS , 2005, Journal of Cancer Research and Clinical Oncology.

[27]  Beni M. Sahai,et al.  Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes , 1989, Nature.

[28]  Dong-Kuk Lee,et al.  Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37. , 2003, Biochemistry.

[29]  G. Daum,et al.  Lipids of mitochondria. , 1985, Biochimica et biophysica acta.

[30]  R. Gennaro,et al.  Cytotoxicity and apoptosis mediated by two peptides of innate immunity. , 1998, Cellular immunology.

[31]  Alan J. Waring,et al.  Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils , 1998, Antimicrobial Agents and Chemotherapy.

[32]  H. Nakayama,et al.  A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. , 2001, Molecular cell.

[33]  J. Cavaillon,et al.  A novel granulocyte-derived peptide with lipopolysaccharide-neutralizing activity. , 1994, Journal of immunology.

[34]  M. Zasloff.  Antimicrobial peptides of multicellular organisms , 2002, Nature.

[35]  W. V. van Blitterswijk,et al.  Comparative lipid analysis of purified plasma membranes and shed extracellular membrane vesicles from normal murine thymocytes and leukemic GRSL cells. , 1982, Biochimica et biophysica acta.

[36]  Paolo Bernardi,et al.  BMAP-28, an Antibiotic Peptide of Innate Immunity, Induces Cell Death through Opening of the Mitochondrial Permeability Transition Pore , 2002, Molecular and Cellular Biology.

[37]  Xu Luo,et al.  Endonuclease G is an apoptotic DNase when released from mitochondria , 2001, Nature.

[38]  H. Lilja,et al.  The Human Cationic Antimicrobial Protein (hCAP-18) Is Expressed in the Epithelium of Human Epididymis, Is Present in Seminal Plasma at High Concentrations, and Is Attached to Spermatozoa , 2000, Infection and Immunity.