pardaxin and Carcinoma

Pardaxin, an antimicrobial peptide secreted by the Red Sea flatfish Pardachirus marmoratus, inhibits proliferation and induces apoptosis of human cancer cell lines. However, the underlying molecular mechanisms are only partially understood at present. In this study, we used proteomic approaches and network reconstruction to clarify the mechanism of pardaxin-induced apoptosis in human cervical carcinoma HeLa cells. We identified that pardaxin-regulated proteins predominantly function in the unfolded protein response, oxidative stress and cytoskeletal distribution. Molecular examination of signal transduction and cellular localization demonstrated that the activator protein-1 transcription factor was activated, which eventually caused apoptosis via both caspase- and apoptosis-inducing factor-dependent pathways. Scavenging of reactive oxygen species (ROS) alleviated c-Jun activation, and small interfering RNA knockdown of c-Jun abrogated pardaxin-induced caspase activation and cell death, thereby implicating ROS and c-Jun in pardaxin-induced apoptosis signaling. In summary, this study provides the first protein-interacting network maps and novel insights into the biological responses and potential toxicity of pardaxin.

Topics: Apoptosis; Apoptosis Inducing Factor; Carcinoma; Caspase 3; Caspase 7; Cell Death; Cell Line; Cell Line, Tumor; Cytoskeletal Proteins; Female; Fish Venoms; Free Radical Scavengers; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases; Oxidative Stress; Phosphorylation; Protein Folding; Protein Transport; Proteomics; Reactive Oxygen Species; Signal Transduction; Transcription Factor AP-1; Unfolded Protein Response; Uterine Cervical Neoplasms

Pardaxin, a pore-forming antimicrobial peptide that encodes 33 amino acids was isolated from the Red Sea Moses sole, Pardachirus mamoratus. In this study, we investigated its antitumor activity in human fibrosarcoma (HT-1080) cells and epithelial carcinoma (HeLa) cells. In vitro results showed that the synthetic pardaxin peptide had antitumor activity in these two types of cancer cells and that 15μg/ml pardaxin did not lyse human red blood cells. Moreover, this synthetic pardaxin inhibited the proliferation of HT1080 cells in a dose-dependent manner and induced programmed cell death in HeLa cells. DNA fragmentation and increases in the subG1 phase and caspase 8 activities suggest that pardaxin caused HeLa cell death by inducing apoptosis, but had a different mechanism in HT1080 cells.

Topics: Amino Acid Sequence; Animals; Apoptosis; Carcinoma; Caspase 8; Cell Proliferation; Cell-Penetrating Peptides; DNA Fragmentation; Erythrocytes; Female; Fibrosarcoma; Fish Proteins; Fish Venoms; Fishes, Poisonous; G1 Phase; HeLa Cells; Humans; Molecular Sequence Data; Neurotoxins; Organ Specificity; Up-Regulation