Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis

  • Authors:
    • Mamoru Akita
    • Miki Suzuki-Karasaki
    • Kyoko Fujiwara
    • Chinatsu Nakagawa
    • Masayoshi Soma
    • Yukihiro Yoshida
    • Toyoko Ochiai
    • Yasuaki Tokuhashi
    • Yoshihiro Suzuki-Karasaki
  • View Affiliations

  • Published online on: August 18, 2014     https://doi.org/10.3892/ijo.2014.2608
  • Pages: 1901-1912
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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer treatment, but some cancer cell types are resistant to TRAIL cytotoxicity. Therefore, overcoming this resistance is necessary for effective TRAIL therapy. Mitochondrial morphology is important for the maintenance of cell function and survival, and is regulated by the delicate balance between fission and fusion. However, the role of mitochondrial morphology dynamics in TRAIL-induced apoptosis is unknown. Here we show that mitochondrial division inhibitor-1 (mdivi-1), an inhibitor of dynamin-related protein1 (Drp1), modulates mitochondrial morphology and TRAIL-induced apoptosis in human cancer cells. mdivi-1 treatment (≥12.5 µM) caused dose- and time‑dependent cell death in malignant melanoma, lung cancer and osteosarcoma cells, while sparing normal cells. mdivi-1 also sensitized cancer cells to TRAIL-induced apoptosis. This potentiation of apoptosis occurred through a caspase-depependent mechanism including the mitochondrial and endoplasmic reticulum (ER) stress pathways. Mdivi-1 potentiated mitochondrial oxidative stress, a major cause of mitochondrial and ER stresses, as evidenced by increases in mitochondrial reactive oxygen species levels, mitochondrial mass, and cardiolipin oxidation. Live cell fluorescence imaging using MitoTracker Red CMXRos revealed that Mdivi-1 caused substantial mitochondrial hyperfusion. Moreover, silencing of Drp1 expression also caused mitochondrial hyperfusion and sensitized cancer cells to TRAIL-induced apoptosis. Our results suggest that cancer cells are more vulnerable than normal cells to a perturbation in mitochondrial morphology dynamics and that this higher susceptibility can be exploited to selectively kill cancer cells and sensitize to TRAIL.
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November-2014
Volume 45 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Akita M, Suzuki-Karasaki M, Fujiwara K, Nakagawa C, Soma M, Yoshida Y, Ochiai T, Tokuhashi Y and Suzuki-Karasaki Y: Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis. Int J Oncol 45: 1901-1912, 2014.
APA
Akita, M., Suzuki-Karasaki, M., Fujiwara, K., Nakagawa, C., Soma, M., Yoshida, Y. ... Suzuki-Karasaki, Y. (2014). Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis. International Journal of Oncology, 45, 1901-1912. https://doi.org/10.3892/ijo.2014.2608
MLA
Akita, M., Suzuki-Karasaki, M., Fujiwara, K., Nakagawa, C., Soma, M., Yoshida, Y., Ochiai, T., Tokuhashi, Y., Suzuki-Karasaki, Y."Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis". International Journal of Oncology 45.5 (2014): 1901-1912.
Chicago
Akita, M., Suzuki-Karasaki, M., Fujiwara, K., Nakagawa, C., Soma, M., Yoshida, Y., Ochiai, T., Tokuhashi, Y., Suzuki-Karasaki, Y."Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis". International Journal of Oncology 45, no. 5 (2014): 1901-1912. https://doi.org/10.3892/ijo.2014.2608