Death-associated protein kinase 3 controls the tumor progression of A549 cells through ERK MAPK/c-Myc signaling

Kake,Satoru; Usui,Tatsuya; Ohama,Takashi; Yamawaki,Hideyuki; Sato,Koichi

doi:10.3892/or.2017.5359

Death-associated protein kinase 3 controls the tumor progression of A549 cells through ERK MAPK/c-Myc signaling

Authors:
- Satoru Kake
- Tatsuya Usui
- Takashi Ohama
- Hideyuki Yamawaki
- Koichi Sato
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Affiliations: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yoshida, Yamaguchi, Japan, Laboratory of Veterinary Toxicology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yoshida, Yamaguchi, Japan, Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan
Published online on: January 9, 2017 https://doi.org/10.3892/or.2017.5359
Pages: 1100-1106

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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.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
4	Bialik S and Kimchi A: The death-associated protein kinases: Structure, function, and beyond. Annu Rev Biochem. 75:189–210. 2006. View Article : Google Scholar : PubMed/NCBI
5	Shani G, Marash L, Gozuacik D, Bialik S, Teitelbaum L, Shohat G and Kimchi A: Death-associated protein kinase phosphorylates ZIP kinase, forming a unique kinase hierarchy to activate its cell death functions. Mol Cell Biol. 24:8611–8626. 2004. View Article : Google Scholar : PubMed/NCBI
6	Tang HW, Wang YB, Wang SL, Wu MH, Lin SY and Chen GC: Atg1-mediated myosin II activation regulates autophagosome formation during starvation-induced autophagy. EMBO J. 30:636–651. 2011. View Article : Google Scholar : PubMed/NCBI
7	Mallipeddi R, Wessagowit V, South AP, Robson AM, Orchard GE, Eady RA and McGrath JA: Reduced expression of insulin-like growth factor-binding protein-3 (IGFBP-3) in Squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 122:1302–1309. 2004. View Article : Google Scholar : PubMed/NCBI
8	Li J, Deng Z, Wang Z, Wang D, Zhang L, Su Q, Lai Y, Li B, Luo Z, Chen X, et al: Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-kB signaling and is associated with metastasis and poor prognosis in gastric cancer patients. Oncotarget. 6:8323–8338. 2015. View Article : Google Scholar : PubMed/NCBI
9	Leister P, Felten A, Chasan AI and Scheidtmann KH: ZIP kinase plays a crucial role in androgen receptor-mediated transcription. Oncogene. 27:3292–3300. 2008. View Article : Google Scholar : PubMed/NCBI
10	Togi S, Ikeda O, Kamitani S, Nakasuji M, Sekine Y, Muromoto R, Nanbo A, Oritani K, Kawai T, Akira S, et al: Zipper-interacting protein kinase (ZIPK) modulates canonical Wnt/beta-catenin signaling through interaction with Nemo-like kinase and T-cell factor 4 (NLK/TCF4). J Biol Chem. 286:19170–19177. 2011. View Article : Google Scholar : PubMed/NCBI
11	Brognard J, Zhang YW, Puto LA and Hunter T: Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-suppressing kinase. Cancer Res. 71:3152–3161. 2011. View Article : Google Scholar : PubMed/NCBI
12	Enjoji S, Yabe R, Fujiwara N, Tsuji S, Vitek MP, Mizuno T, Nakagawa T, Usui T, Ohama T and Sato K: The therapeutic effects of SET/I2PP2A inhibitors on canine melanoma. J Vet Med Sci. 77:1451–1456. 2015. View Article : Google Scholar : PubMed/NCBI
13	Usui T, Nijima R, Sakatsume T, Otani K, Kameshima S, Okada M and Yamawaki H: Eukaryotic elongation factor 2 kinase controls proliferation and migration of vascular smooth muscle cells. Acta Physiol. 213:472–480. 2015. View Article : Google Scholar
14	Yabe R, Miura A, Usui T, Mudrak I, Ogris E, Ohama T and Sato K: Protein phosphatase methyl-esterase PME-1 protects protein phosphatase 2A from ubiquitin/proteasome degradation. PLoS One. 10:e01452262015. View Article : Google Scholar : PubMed/NCBI
15	Usui T, Sakatsume T, Nijima R, Otani K, Kazama K, Morita T, Kameshima S, Okada M and Yamawaki H: Death-associated protein kinase 3 mediates vascular structural remodelling via stimulating smooth muscle cell proliferation and migration. Clin Sci. 127:539–548. 2014. View Article : Google Scholar : PubMed/NCBI
16	Hunter T and Pines J: Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 79:573–582. 1994. View Article : Google Scholar : PubMed/NCBI
17	Bravo-Cordero JJ, Hodgson L and Condeelis J: Directed cell invasion and migration during metastasis. Curr Opin Cell Biol. 24:277–283. 2012. View Article : Google Scholar : PubMed/NCBI
18	Scheel C and Weinberg RA: Cancer stem cells and epithelial-mesenchymal transition: Concepts and molecular links. Semin Cancer Biol. 22:396–403. 2012. View Article : Google Scholar : PubMed/NCBI
19	Kawai T, Matsumoto M, Takeda K, Sanjo H and Akira S: ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. Mol Cell Biol. 18:1642–1651. 1998. View Article : Google Scholar : PubMed/NCBI
20	Guin S, Ru Y, Wynes MW, Mishra R, Lu X, Owens C, Barn AE, Vasu VT, Hirsch FR, Kern JA, et al: Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression. J Thorac Oncol. 8:1492–1501. 2013. View Article : Google Scholar : PubMed/NCBI
21	Oneyama C, Ikeda J, Okuzaki D, Suzuki K, Kanou T, Shintani Y, Morii E, Okumura M, Aozasa K and Okada M: MicroRNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways. Oncogene. 30:3489–3501. 2011. View Article : Google Scholar : PubMed/NCBI
22	An S, Yang Y, Ward R, Liu Y, Guo XX and Xu TR: A-Raf: A new star of the family of raf kinases. Crit Rev Biochem Mol Biol. 50:520–531. 2015. View Article : Google Scholar : PubMed/NCBI
23	Endo A, Surks HK, Mochizuki S, Mochizuki N and Mendelsohn ME: Identification and characterization of zipper-interacting protein kinase as the unique vascular smooth muscle myosin phosphatase-associated kinase. J Biol Chem. 279:42055–42061. 2004. View Article : Google Scholar : PubMed/NCBI
24	Tsai YT, Chuang MJ, Tang SH, Wu ST, Chen YC, Sun GH, Hsiao PW, Huang SM, Lee HJ, Yu CP, et al: Novel cancer therapeutics with allosteric modulation of the mitochondrial C-Raf-DAPK complex by Raf inhibitor combination therapy. Cancer Res. 75:3568–3582. 2015. View Article : Google Scholar : PubMed/NCBI
25	Ku MJ, Kim JH, Lee J, Cho JY, Chun T and Lee SY: Maclurin suppresses migration and invasion of human non-small-cell lung cancer cells via anti-oxidative activity and inhibition of the Src/FAK-ERK-β-catenin pathway. Mol Cell Biochem. 402:243–252. 2015. View Article : Google Scholar : PubMed/NCBI
26	Usui T, Okada M, Hara Y and Yamawaki H: Death-associated protein kinase 3 mediates vascular inflammation and development of hypertension in spontaneously hypertensive rats. Hypertension. 60:1031–1039. 2012. View Article : Google Scholar : PubMed/NCBI
27	Marcus AI and Zhou W: LKB1 regulated pathways in lung cancer invasion and metastasis. J Thorac Oncol. 5:1883–1886. 2010. View Article : Google Scholar : PubMed/NCBI