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Co-delivery of LETM1 and CTMP synergistically inhibits tumor growth in H-ras12V liver cancer model mice

Cited 9 time in Web of Science Cited 10 time in Scopus
Authors
Shin, J-Y; Chung, Y-S; Kang, B.; Jiang, H-L; Yu, D-Y; Han, K.; Chae, C.; Moon, J-H; Jang, G.; Cho, Myung-Haing
Issue Date
2013-03
Citation
Cancer Gene Therapy, Vol.20 No.3, pp.186-194
Keywords
2A-peptideCTMPGPCSLETM1liver cancer
Abstract
As hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, development of novel therapeutic approaches for HCC is urgently needed. Two different genes, LETM1 and CTMP, which target mitochondrial functions, were chosen and linked using 2A-peptide sequence. Successful self-cleavage of 2A-peptide induced synergistic antitumor effect in the liver of H-ras12V, the HCC model mice, by simultaneous activation of LETM1 (Leucine zipper/EF hand-containing transmembrane-1) and CTMP (carboxyl-terminal modulator protein). Overexpression of LETM1 and CTMP significantly reduced the incidence of tumorigenesis, which were confirmed by gross and microscopic observations. Morphological changes in mitochondria, such as swelling and loss of cristae, were significant, and the prolonged activation of defects in mitochondrial function led to mitochondria-mediated apoptosis. Furthermore, with CTMP as a direct binding partner of Akt1, and LETM1 as a binding partner of CTMP, LETM1-2A-CTMP downregulated the Akt1 pathway at both Ser473 and Thr308 sites of phosphorylation. Proliferation and angiogenesis, which are important in cancer prognosis, were reduced in tumor sites after introduction of LETM1-2A-CTMP. Taken together, the results indicate that introduction of the mitochondria-targeting genes, LETM1 and CTMP, and self-processing capacity of 2A-peptide sequence exerts an antitumor effect in liver of H-ras12V mice, suggesting its potential as a tool for gene therapy. Cancer Gene Therapy (2013) 20, 186-194; doi:10.1038/cgt.2013.6; published online 8 February 2013
ISSN
0929-1903
URI
http://hdl.handle.net/10371/172351
DOI
https://doi.org/10.1038/cgt.2013.6
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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