Abstract
BackgroundLeucine zipper/EF hand-containing transmembrane-1 (LETM1) encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. However, a previous study demonstrated that LETM1 served as an anchor protein for complex formation between mitochondria and ribosome, and regulated mitochondrial biogenesis.Methodology/Principal FindingsTherefore, we examine the possibility that LETM1 may function to regulate mitochondria and lung tumor growth. In this study, we addressed this question by studying in the effect of adenovirus-mediated LETM1 in the lung cancer cell and lung cancer model mice. To investigate the effects of adenovirus-LETM1 in vitro, we infected with adenovirus-LETM1 in A549 cells. Additionally, in vivo effects of LETM1 were evaluated on K-ras LA1 mice, human non-small cell lung cancer model mice, by delivering the LETM1 via aerosol through nose-only inhalation system. The effects of LETM1 on lung cancer growth and AMPK related signals were evaluated. Adenovirus-mediated overexpression of LETM1 could induce destruction of mitochondria of lung cancer cells through depleting ATP and AMPK activation. Furthermore, adenoviral-LETM1 also altered Akt signaling and inhibited the cell cycle while facilitating apoptosis. Theses results demonstrated that adenovirus-LETM1 suppressed lung cancer cell growth in vitro and in vivo.Conclusions/SignificanceAdenovirus-mediated LETM1 may provide a useful target for designing lung tumor prevention and treatment.
Highlights
Lung cancer is the leading cause of cancer deaths in the world with over one million cases diagnosed every year
Analysis of relative mitochondrial ATP amounts using COX-8 luciferase revealed that the mitochondrial ATP level was significantly reduced in Leucine zipper/EF hand-containing transmembrane-1 (LETM1) overexpressed cells compared to control (Fig. 1C), indicating that LETM1 inhibited the production of mitochondrial ATP
Since AMPK is activated to reserve cellular energy content as described earlier, we investigated the changes in protein expression of total AMPK, phosphoAMPK at Thr 172 by LETM1 overexpression
Summary
Lung cancer is the leading cause of cancer deaths in the world with over one million cases diagnosed every year. Multiple options for the treatment of lung cancer have been described, including surgery, chemotherapy, and radiation, therapeutic effect is typically transient and mostly absent with advanced disease [1,2]. The need of more rational approach to lung cancer therapy is essential. Mitochondria have emerged as effective target for anti-cancer therapy [3]. Mitochondria function as central components of cell survival through ATP production and govern cell fate by mitochondrial membrane-dependent cell death signal [5]. Leucine zipper/EF hand-containing transmembrane-1 (LETM1) encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. A previous study demonstrated that LETM1 served as an anchor protein for complex formation between mitochondria and ribosome, and regulated mitochondrial biogenesis
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