title: Death-associated protein kinase 3 controls the tumor progression of A549 cells through ERK MAPK/c-Myc signaling.
abstract: Death-associated protein kinases (DAPKs) are members of the serine/threonine protein kinase family, which regulate cell death. Although DAPK3 has been implicated as a tumor suppressor, a recent study revealed an oncogenic role of DAPK3. However, the role of DAPK3 in non-small cell lung cancer (NSCLC) remains unclear. Therefore, we examined whether DAPK3 controls the progression of NSCLC using the NSCLC cell line, A549. We generated A549 cells stably expressing small hairpin RNA (shRNA) targeting DAPK3. In the A549 cells, the protein level of DAPK3 was decreased and the cell proliferation was inhibited. DAPK3 knockdown caused G1/G0 cell cycle arrest as assessed by flow cytometric assay and reduced cyclin D1 expression in A549 cells. Phosphorylation of ERK and c-Myc, but not Akt and JNK, was inhibited by DAPK3 knockdown. Cell migration and invasion were also inhibited by DAPK3 knockdown as determined by a Boyden chamber assay and an invasion assay, respectively. Moreover, DAPK3 knockdown inhibited anchorage-independent cell growth as determined by soft-agar colony formation assay. In a mouse xenograft model, tumors derived from DAPK3-knockdown cells exhibited reduced tumor growth. The present results demonstrated for the first time that DAPK3 controls proliferation, migration, invasion, soft‑agar colony formation and tumor growth through activation of ERK/c-Myc signaling in A549 cells. These findings indicate that DAPK3 may be a novel target for the treatment of NSCLC.
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yoshida, Yamaguchi, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kake
authors.affiliation: Laboratory of Veterinary Toxicology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yoshida, Yamaguchi, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yoshida, Yamaguchi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yoshida, Yamaguchi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016688:Mice, Inbred NOD; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D016271:Proto-Oncogene Proteins c-myc; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases