Abstract
TOM40 is a channel-forming subunit of translocase, which is essential for the movement of proteins into the mitochondria. We found that TOM40 was highly expressed in epithelial ovarian cancer (EOC) cells at both the transcriptional and translational levels; its expression increased significantly during the transformation from normal ovarian epithelial cells to EOC (p < 0.001), and TOM40 expression negatively correlated with disease-free survival (Hazard ratio = 1.79, 95% Confidence inerval 1.16–2.78, p = 0.009). TOM40 knockdown decreased proliferation in several EOC cell lines and reduced tumor burden in an in vivo xenograft mouse model. TOM40 expression positively correlated with intracellular adenosine triphosphate (ATP) levels. The low ATP and high reactive oxygen species (ROS) levels increased the activity of AMP-activated protein kinase (AMPK) in TOM40 knockdown EOC cells. However, AMPK activity did not correlate with declined cell growth in TOM40 knockdown EOC cells. We found that metformin, first-line therapy for type 2 diabetes, effectively inhibited the growth of EOC cell lines in an AMPK-independent manner by inhibiting mitochondria complex I. In conclusion, TOM40 positively correlated with mitochondrial activities, and its association enhances the proliferation of ovarian cancer. Also, metformin is an effective therapeutic option in TOM40 overexpressed ovarian cancer than normal ovarian epithelium.
Highlights
Mitochondria are intracellular organelles that play important roles in various cellular metabolic processes such as adenosine triphosphate (ATP) production, iron homeostasis, small-molecule biosynthesis, and cellular redox status maintenance [1]
TOM40 mRNA levels were significantly higher in epithelial ovarian cancer (EOC) cell lines than in immortalized HOSEs (iHOSE) cells, (5.36-fold, p = 0.0207) (Figure 1A)
The TOM40 protein expression significantly increased in EOC cells compared to iHOSE cells when normalized to α-actinin (4.12-fold, p = 0.0173) (Figure 1B)
Summary
Mitochondria are intracellular organelles that play important roles in various cellular metabolic processes such as ATP production, iron homeostasis, small-molecule biosynthesis, and cellular redox status maintenance [1]. Of the 1000 to 1500 known mitochondrial proteins, 36 are encoded in the mitochondrial DNA. The remaining proteins translocate to the mitochondria after synthesis in the cytosol and are encoded by the nuclear DNA [2,3]. Each mitochondrion consists of a single outer membrane and an inner membrane, which form an aqueous intermembrane space and matrix [4]. Outer membrane protein channels, such as the translocase of the outer membrane (TOM) complex, determine whether mitochondrial proteins localize to the interior of the mitochondria or the mitochondrial membrane [4,5,6].
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