Expression of programmed cell death 5 protein inhibits progression of lung carcinoma in vitro and in vivo via the mitochondrial apoptotic pathway

Xu,Shining; Sui,Gang; Yuan,Lei; Zou,Zhiqiang

doi:10.3892/mmr.2014.2454

Expression of programmed cell death 5 protein inhibits progression of lung carcinoma in vitro and in vivo via the mitochondrial apoptotic pathway

Authors:
- Shining Xu
- Gang Sui
- Lei Yuan
- Zhiqiang Zou
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Affiliations: Department of Thoracic Surgery, The General Hospital of Jinan Military Command, Jinan, Shandong 250031, P.R. China
Published online on: August 5, 2014 https://doi.org/10.3892/mmr.2014.2454
Pages: 2059-2064

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Abstract

Lung cancer is one of the most common and serious types of cancer, and is characterized by uncontrolled cell growth and metastasis from lung tissues to other body parts. The programmed cell death 5 (Pdcd5) protein is known to accelerate apoptosis in different cell types of tumor. The aim of the present study was to explore the role of Pdcd5 in lung carcinoma and to identify the mechanisms underlying the antitumorigenic properties of Pdcd5 in lung cancer. First, we detected and compared the expression of Pdcd5 in healthy and highly differentiated adenocarcinoma lung tissues. The results of histochemical staining and western blot analysis demonstrated that Pdcd5 expression is markedly decreased in highly differentiated lung adenocarcinoma. Next, we used the lung adenocarcinoma cell line A549 to study the effects of Pdc5 expression on proliferation and colony formation. The results revealed that the expression of Pdcd5 significantly inhibits cell proliferation and colony formation in A549 cells. Importantly, Pdcd5 expression induced tumor cell apoptosis, and the apoptotic proteins caspase-3 and -9 were activated. The expression of B-cell lymphoma 2 (Bcl-2) was reduced and that of Bcl2‑associated X protein (Bax) was increased, overall suggesting that the intrinsic apoptotic pathway is activated. Furthermore, using a mice xenograft model and vectors for stable expression or silencing of Pdcd5, we showed that stable expression of the protein significantly increases the survival rate of mice in vivo (P<0.01 compared to control). In conclusion, both in vitro and in vivo experiments demonstrated that Pdcd5 expression inhibits proliferation and induces apoptosis in the A549 cell line, indicating that the Pdcd5 protein may play an important role in the progression of lung cancer. Therefore, Pdcd5 may be a promising target for the therapy of lung carcinoma.

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1	Marshall HM, Bowman RV, Yang IA, Fong KM and Berg CD: Screening for lung cancer with low-dose computed tomography: a review of current status. J Thorac Dis. 5:S524–S539. 2013.PubMed/NCBI
2	Lee PN and Forey BA: Indirectly estimated absolute lung cancer mortality rates by smoking status and histological type based on a systematic review. BMC Cancer. 13:1892013. View Article : Google Scholar
3	Amorin Kajatt E: Lung cancer: a review of current knowledge, diagnostic methods and therapeutic perspectives. Rev Peru Med Exp Salud Publica. 30:85–92. 2013.(In Spanish).
4	Centers for Disease Control and Prevention (CDC). State-specific trends in lung cancer incidence and smoking - United States, 1999–2008. MMWR Morb Mortal Wkly Rep. 60:1243–1247. 2011.PubMed/NCBI
5	Jankovic M, Samarzija M, Jakopovic M, Kulis T and Znaor A: Trends in lung cancer incidence and mortality in Croatia, 1988–2008. Croat Med J. 53:93–99. 2012.PubMed/NCBI
6	Kern DG, Kern E, Crausman RS and Clapp RW: A retrospective cohort study of lung cancer incidence in nylon flock workers, 1998–2008. Int J Occup Environ Health. 17:345–351. 2011.PubMed/NCBI
7	Han R, Zheng R, Zhang S, Wu M and Chen W: Trend analyses on the differences of lung cancer incidence between gender, area and average age in China during 1989–2008. Zhongguo Fei Ai Za Zhi. 16:445–451. 2013.(In Chinese).
8	Chang S, Dai M, Ren JS, Chen YH and Guo LW: Estimates and prediction on incidence, mortality and prevalence of lung cancer in China in 2008. Zhonghua Liu Xing Bing Xue Za Zhi. 33:391–394. 2012.(In Chinese).
9	She J, Yang P, Hong Q and Bai C: Lung cancer in China: challenges and interventions. Chest. 143:1117–1126. 2013. View Article : Google Scholar : PubMed/NCBI
10	Huncharek M, Muscat J and Geschwind JF: K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases. Carcinogenesis. 20:1507–1510. 1999. View Article : Google Scholar : PubMed/NCBI
11	Suda K, Tomizawa K, Osada H, et al: Conversion from the ‘oncogene addiction’ to ‘drug addiction’ by intensive inhibition of the EGFR and MET in lung cancer with activating EGFR mutation. Lung Cancer. 76:292–299. 2012.
12	You L, He B, Xu Z, et al: Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells. Oncogene. 23:6170–6174. 2004. View Article : Google Scholar : PubMed/NCBI
13	Xu L, Hu J, Zhao Y, et al: PDCD5 interacts with p53 and functions as a positive regulator in the p53 pathway. Apoptosis. 17:1235–1245. 2012. View Article : Google Scholar : PubMed/NCBI
14	Liu H, Wang Y, Zhang Y, et al: TFAR19, a novel apoptosis-related gene cloned from human leukemia cell line TF-1, could enhance apoptosis of some tumor cells induced by growth factor withdrawal. Biochem Biophys Res Commun. 254:203–210. 1999. View Article : Google Scholar
15	Chen CH, Jiang Z, Yan JH, et al: The involvement of programmed cell death 5 (PDCD5) in the regulation of apoptosis in cerebral ischemia/reperfusion injury. CNS Neurosci Ther. 19:566–576. 2013. View Article : Google Scholar : PubMed/NCBI
16	Gao F, Ding L, Zhao M, Qu Z, Huang S and Zhang L: The clinical significance of reduced programmed cell death 5 expression in human gastrointestinal stromal tumors. Oncol Rep. 28:2195–2199. 2012.PubMed/NCBI
17	Zhuge C, Chang Y, Li Y, Chen Y and Lei J: PDCD5-regulated cell fate decision after ultraviolet-irradiation-induced DNA damage. Biophys J. 101:2582–2591. 2011. View Article : Google Scholar : PubMed/NCBI
18	Shi L, Song Q, Zhang Y, et al: Potent antitumor activities of recombinant human PDCD5 protein in combination with chemotherapy drugs in K562 cells. Biochem Biophys Res Commun. 396:224–230. 2010. View Article : Google Scholar : PubMed/NCBI
19	Saleem M, Maddodi N, Abu Zaid M, et al: Lupeol inhibits growth of highly aggressive human metastatic melanoma cells in vitro and in vivo by inducing apoptosis. Clin Cancer Res. 14:2119–2127. 2008. View Article : Google Scholar : PubMed/NCBI
20	Adhami VM, Siddiqui IA, Ahmad N, Gupta S and Mukhtar H: Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. Cancer Res. 64:8715–8722. 2004. View Article : Google Scholar
21	Ahmadian S, Barar J, Saei AA, Fakhree MA and Omidi Y: Cellular toxicity of nanogenomedicine in MCF-7 cell line: MTT assay. J Vis Exp. 26:e11912009. View Article : Google Scholar
22	Verma A, Prasad KN, Singh AK, Nyati KK, Gupta RK and Paliwal VK: Evaluation of the MTT lymphocyte proliferation assay for the diagnosis of neurocysticercosis. J Microbiol Methods. 81:175–178. 2010. View Article : Google Scholar : PubMed/NCBI
23	Seidl K and Zinkernagel AS: The MTT assay is a rapid and reliable quantitative method to assess Staphylococcus aureus induced endothelial cell damage. J Microbiol Methods. 92:307–309. 2013. View Article : Google Scholar : PubMed/NCBI
24	Nishitani H, Sugimoto N, Roukos V, et al: Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J. 25:1126–1136. 2006. View Article : Google Scholar : PubMed/NCBI
25	Peng L, Xu Z, Zhou Y, Yang T, Liang ZQ and Zhang M: Effect of rosiglitazone on cells cycle, apoptosis and expression of Skp2 and p27Kip1 in hepatocellular carcinoma cell line. Zhonghua Gan Zang Bing Za Zhi. 18:148–149. 2010.(In Chinese).
26	Schulman BA, Carrano AC, Jeffrey PD, et al: Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature. 408:381–386. 2000. View Article : Google Scholar : PubMed/NCBI
27	Cheng A, Wang Y, Ma D, Zhou H and Lou S: Characterization of programmed cell death 5 (PDCD5) gene in human cartilage and its possible significance. Beijing Da Xue Xue Bao. 35:481–484. 2003.(In Chinese).
28	Ruan GR, Qin YZ, Chen SS, et al: Abnormal expression of the programmed cell death 5 gene in acute and chronic myeloid leukemia. Leuk Res. 30:1159–1165. 2006. View Article : Google Scholar : PubMed/NCBI
29	Li H, Wang Q, Gao F, et al: Reduced expression of PDCD5 is associated with high-grade astrocytic gliomas. Oncol Rep. 20:573–579. 2008.PubMed/NCBI
30	Du YJ, Xiong L, Lou Y, Tan WL and Zheng SB: Reduced expression of programmed cell death 5 protein in tissue of human prostate cancer. Chin Med Sci J. 24:241–245. 2009. View Article : Google Scholar : PubMed/NCBI
31	Gao F, Ding L, Zhao M, Qu Z, Huang S and Zhang L: The clinical significance of reduced programmed cell death 5 expression in human gastrointestinal stromal tumors. Oncol Rep. 28:2195–2199. 2012.PubMed/NCBI
32	Chen C, Zhou H, Xu L, et al: Recombinant human PDCD5 sensitizes chondrosarcomas to cisplatin chemotherapy in vitro and in vivo. Apoptosis. 15:805–813. 2010. View Article : Google Scholar : PubMed/NCBI
33	Yin A, Jiang Y, Zhang X, Zhao J and Luo H: Transfection of PDCD5 sensitizes colorectal cancer cells to cisplatin-induced apoptosis in vitro and in vivo. Eur J Pharmacol. 649:120–126. 2010. View Article : Google Scholar : PubMed/NCBI