TOM40 inhibits ovarian cancer cell growth by modulating mitochondrial function including intracellular ATP and ROS levels

Wookyeom Yang, Ha Yeon Shin, Hanbyoul Cho, Joon Yong Chung, Eun Ju Lee, Jae Hoon Kim, Eun Suk Kang

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12 Citations (Scopus)


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.

Original languageEnglish
Article number1329
Issue number5
Publication statusPublished - 2020 May

Bibliographical note

Funding Information:
Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2017R1D1A1A09000576, NRF-2017R1A2B2008505, and NRF-2019R1A6A3A13092928) and Korean Gynecologic Onoclogy Group (KGOG).

Funding Information:
A total of 336 patients diagnosed with ovarian tumors (84 benign, 51 borderline, and 201 cancerous) at Gangnam Severance Hospital (Seoul, Republic of Korea) were enrolled in this study between 1993 and 2014. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of the National Research Foundation (NRF) funded by the Korean government (MSIT) (NRF-2017M3A9B8069610). Before beginning the study, approval was obtained from the Institutional Review Board of Gangnam Severance Hospital (IRB No. 3-2010-0030 and 3-2011-0057), and written consent to participate in the study was obtained from each person. Detailed immunohistochemistry (IHC) protocols were performed as described previously [56]. Briefly, sections were incubated with rabbit polyclonal anti-TOM40 antibody (Cat. 18409-1-AP; Proteintech Group, Inc, Rosemont, IL, USA) at a dilution of 1:150, overnight at 4 ◦C. Negative controls omitted the primary antibody. Human testicular tissue was used as a positive control for TOM40 immunoreactivity. The stained sections were digitized utilizing the NanoZoomer 2.0 HT (Hamamatsu Photonics K.K., Hamamatzu, Japan) at ×20 objective magnification (0.5 µm resolution). For tissue microarrays, digital analysis of TOM40 IHC was performed using Visiopharm software v4.5.1.324 (Visiopharm, Hørsholm, Denmark). 3,3’-diaminobenzidine (DAB) (brown staining) intensity (0 = negative, 1 = weak, 2 = moderate, and 3 = strong) was obtained using a predefined algorithm and optimized settings. The overall histoscore was calculated as the percentage of positive cells multiplied by their staining intensity (possible range 0–300) [57]. The cutoff values of histoscore were defined by considering the distribution and prognostic significance of the values.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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