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

Cancer Gene Therapy volume 20, pages 186–194 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by National Research Foundation grant funded by the Korea government (MEST) (No. 2012M3A9B6055304) and partially supported by the Research Institute for Veterinary Science, Seoul National University.

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The funders had no role in the study design, data collection or analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, Korea

    J-Y Shin, Y-S Chung, B Kang & M-H Cho

  2. School of Pharmacy, China Pharmaceutical University, Nanjing, China

    H-L Jiang

  3. Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea

    D-Y Yu

  4. Laboratory of Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea

    K Han & C Chae

  5. Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Seoul National University, Seoul, Korea

    J-H Moon & G Jang

  6. Emergence Center for Food-Medicine Personalized Therapy System, Advanced Institutes of Convergence Technology, Seoul National University, Gyeonggi-do, Korea

    G Jang

  7. Department of Nano Fusion Technology, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Korea

    M-H Cho

  8. Graduate Group of Tumor Biology, Seoul National University, Seoul, Korea

    M-H Cho

  9. Advanced Institute of Convergence Technology, Seoul National University, Suwon, Korea

    M-H Cho

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Shin, JY., Chung, YS., Kang, B. et al. Co-delivery of LETM1 and CTMP synergistically inhibits tumor growth in H-ras12V liver cancer model mice. Cancer Gene Ther 20, 186–194 (2013). https://doi.org/10.1038/cgt.2013.6

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