title: PERP gene therapy attenuates lung cancer xenograft via inducing apoptosis and suppressing VEGF.
abstract: Inducing apoptosis is an attractive antitumor strategy. PERP is an apoptosis-associated target of p53, and its activation alone is sufficient to induce apoptotic pathway leading to cell death. We have previously demonstrated that overexpression of PERP in tumor cell lines with low intrinsic PERP activity suppressed cancer cell growth and enhanced sensitivity to chemotherapeutical agents. We further identified that PERP was present in surgical normal lung tissue, but absent in cancerous tissue of the same patient. Here, we sought to investigate the anti-tumor effects of PERP gene therapy in vivo. Then nude mice were transplanted with p53-mutanted Anip973 human lung cancer xenografts and treated with normal saline, pcDNA3.1 (vector) and pcDNA3.1-PERP, respectively. Successful transfection and robust expression of PERP was detected. Treatment with pcDNA3.1-PERP increased apoptosis and retarded growth in the xenografts, which contributed to a 55% decrease in tumor volume compared with controls. Furthermore, PERP gene therapy activated pro-apoptotic Caspase-3 cascade and upregulated the expression of the second mitochondria-derived activator of caspase (Smac) and human TNF-related apoptosis-inducing ligand (TRAIL), while suppressed vascular endothelial growth factor (VEGF) expression, indicating apoptosis and anti-angiogenesis are involved in the inhibitory effect of the PERP gene therapy. Taken together, our results suggest PERP gene therapy may supply an alternative strategy for lung adenocarcinoma management. Furthermore, Anip973 is a p53-mutanted cell line and the findings of this study provide reference value for other p53-mutanted cancers which is common among malignant tumors.
authors.affiliation: Institute of Cancer Research, University of South China, Hengyang City, China. chenke@big.ac.cn
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Luo
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Li
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Liu
authors.forename: Qingzheng
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C416404:PERP protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D053148:Caspase 3