Dual expression of shAkt1 and Pdcd4 suppresses lung tumorigenesis in K-rasLA1 mice

Seong-Ho Hong; Jae-Ho Lee; Hu-Lin Jiang; Ji-Eun Kim; Ah Young Lee; Sanghwa Kim; Chong-Su Cho; Myung-Haing Cho

Dual expression of shAkt1 and Pdcd4 suppresses lung tumorigenesis in K-rasLA1 mice

Anticancer Res. 2015 Apr;35(4):2015-9.

Authors

Seong-Ho Hong¹, Jae-Ho Lee¹, Hu-Lin Jiang², Ji-Eun Kim¹, Ah Young Lee¹, Sanghwa Kim³, Chong-Su Cho⁴, Myung-Haing Cho⁵

Affiliations

¹ Laboratory of Toxicology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
² State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, P.R. China.
³ Laboratory of Toxicology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea Graduate Group of Tumor Biology, Seoul National University, Seoul, Republic of Korea.
⁴ Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.
⁵ Laboratory of Toxicology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea Graduate school of Convergence Science and Technology, Seoul National University, Suwon, Republic of Korea Graduate Group of Tumor Biology, Seoul National University, Seoul, Republic of Korea Advanced Institute of Convergence Technology, Seoul National University, Suwon, Republic of Korea Institute of GreenBio Science Technology, Seoul National University, Pyeongchang-gun, Ganghon-do, Republic of Korea mchotox@snu.ac.kr.

PMID: 25862855

Abstract

Background/aim: Lung cancer has the highest mortality rate among cancers and current therapies are not efficient. Therefore, novel therapeutic methods are urgently needed. Here, we examined the effectiveness of simultaneous Akt1 inhibition and Pdcd4 over-expression using a dual expression system in suppressing tumorigenesis in K-ras(LA1) mice (a lung cancer model).

Materials and methods: An shRNA targeting Akt1 (shAkt1) and cDNA of programmed cell death protein 4 (Pdcd4) were inserted into a dual expression vector (shAkt1+Pdcd4). A sorbitol diacrylate-polyethylenimine (SDA-PEI) carrier was used because of low toxicity and high transfection efficiency. Aerosolized SDA-PEI/shAkt1+Pdcd4 complex was delivered to the mice twice a week for 4 weeks using a nose-only exposure inhalation chamber.

Results: Simultaneous Akt1 inhibition and Pdcd4 over-expression synergistically induced potent antitumor effect. Analysis revealed significant reduction in lung tumor number.

Conclusion: Dual expression of shAkt1 and Pdcd4 effectively suppresses lung tumorigenesis.

Keywords: Lung cancer; PDCD4; aerosol delivery; gene therapy; shAkt1; sorbitol diacrylate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / biosynthesis*
Apoptosis Regulatory Proteins / immunology
Carcinogenesis / genetics
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Gene Transfer Techniques
Genetic Therapy*
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Lung Neoplasms / therapy*
Mice
Oncogene Protein p21(ras) / genetics
Polyethyleneimine / administration & dosage
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / genetics*
RNA, Small Interfering / genetics
RNA-Binding Proteins / biosynthesis*
RNA-Binding Proteins / immunology

Substances

Apoptosis Regulatory Proteins
Pdcd4 protein, mouse
RNA, Small Interfering
RNA-Binding Proteins
Polyethyleneimine
Akt1 protein, mouse
Proto-Oncogene Proteins c-akt
Oncogene Protein p21(ras)