The mechanisms by which pardaxin, a natural cationic antimicrobial peptide, targets the endoplasmic reticulum and induces c-FOS.
Pardaxin is a cationic antimicrobial peptide derived from Red Sea Moses sole. Previous studies have shown that pardaxin selectively triggers the death of cancer cells, initiating the development of a pardaxin-based cancer vaccine; however, the underlying mechanism by which pardaxin kills cancer cells has not yet been elucidated. Here, we demonstrate that this mechanism involves endoplasmic reticulum (ER) targeting and c-FOS induction. Transcriptiome analysis of pardaxin-treated HT-1080 cells revealed induction of the gene encoding c-FOS, an AP-1 transcription factor. Pardaxin mediates cell death by activating c-FOS, but not other AP-1 transcription factors. Overexpression of c-FOS caused a dramatic increase in cell death, while knockdown of c-FOS induced pardaxin resistance; such effects were observed in both an in vitro cell model and an in vivo xenograft tumor model. Treatment with pardaxin also increased the level of calcium, and blockage of cellular calcium signaling disrupted pardaxin-induced cell death. Immunocytochemistry was used to demonstrate targeting of pardaxin to the endoplasmic reticulum, but not to the Golgi apparatus or mitochondria. Importantly, pardaxin treatment or c-FOS overexpression induced cell death in diverse cancer cell lines, indicating that pardaxin and c-FOS may possess therapeutic potential for use in cancer treatment.
Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, 23-10 Dahuen Road, Jiaushi, Ilan 262, Taiwan.
Chen-Hung
CH
Ting
Department of Food Science, National Taiwan Ocean University, 2, Pei-Ning Road, Keelung 202, Taiwan.
Han-Ning
HN
Huang
Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taiwan.
Tsui-Chin
TC
Huang
Department of Food Science, National Taiwan Ocean University, 2, Pei-Ning Road, Keelung 202, Taiwan.
Chang-Jer
CJ
Wu
Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, 23-10 Dahuen Road, Jiaushi, Ilan 262, Taiwan. Electronic address: zoocjy@gate.sinica.edu.tw.
Jyh-Yih
JY
Chen
D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005397:Fish Venoms / Q000737:chemistry / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D005397:Fish Venoms; D016760:Proto-Oncogene Proteins c-fos; C017603:pardaxin
Calcium; Cationic antimicrobial peptide; Endoplasmic reticulum; Pardaxin; c-FOS