Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities

  • Authors:
    • Yohei Ohshima
    • Natsuhiko Takata
    • Miki Suzuki-Karasaki
    • Yukihiro Yoshida
    • Yasuaki Tokuhashi
    • Yoshihiro Suzuki-Karasaki
  • View Affiliations

  • Published online on: August 11, 2017     https://doi.org/10.3892/ijo.2017.4096
  • Pages:1146-1158
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Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent with high tumor-selective cytotoxicity. The congenital and acquired resistance of some cancer types including malignant melanoma and osteosarcoma impede the current TRAIL therapy of these cancers. Since fine tuning of the intracellular Ca2+ level is essential for cell function and survival, Ca2+ dynamics could be a promising target for cancer treatment. Recently, we demonstrated that mitochondrial Ca2+ removal increased TRAIL efficacy toward malignant melanoma and osteosarcoma cells. Here we report that mitochondrial Ca2+ overload leads to tumor-selective sensitization to TRAIL cytotoxicity. Treatment with the mitochondrial Na+/Ca2+ exchanger inhibitor CGP-37157 and oxidative phosphorylation inhibitor antimycin A and FCCP resulted in a rapid and persistent mitochondrial Ca2+ rise. These agents also increased TRAIL sensitivity in a tumor-selective manner with a switching from apoptosis to a nonapoptotic cell death. Moreover, we found that mitochondrial Ca2+ overload led to increased mitochondrial fragmentation, while mitochondrial Ca2+ removal resulted in mitochondrial hyperfusion. Regardless of their reciprocal actions on the mitochondrial dynamics, both interventions commonly exacerbated TRAIL-induced mitochondrial network abnormalities. These results expand our previous study and suggest that an appropriate level of mitochondrial Ca2+ is essential for maintaining the mitochondrial dynamics and the survival of these cells. Thus, disturbing mitochondrial Ca2+ homeostasis may serve as a promising approach to overcome the TRAIL resistance of these cancers with minimally compromising the tumor-selectivity.

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October 2017
Volume 51 Issue 4

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

2016 Impact Factor: 3.079
Ranked #33/217 Oncology
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APA
Ohshima, Y., Takata, N., Suzuki-Karasaki, M., Yoshida, Y., Tokuhashi, Y., & Suzuki-Karasaki, Y. (2017). Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities. International Journal of Oncology, 51, 1146-1158. https://doi.org/10.3892/ijo.2017.4096
MLA
Ohshima, Y., Takata, N., Suzuki-Karasaki, M., Yoshida, Y., Tokuhashi, Y., Suzuki-Karasaki, Y."Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities". International Journal of Oncology 51.4 (2017): 1146-1158.
Chicago
Ohshima, Y., Takata, N., Suzuki-Karasaki, M., Yoshida, Y., Tokuhashi, Y., Suzuki-Karasaki, Y."Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities". International Journal of Oncology 51, no. 4 (2017): 1146-1158. https://doi.org/10.3892/ijo.2017.4096