Open Access

Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K+ channels and endoplasmic reticulum stress

  • Authors:
    • Yoshihiro Suzuki
    • Toshio Inoue
    • Mayumi Murai
    • Miki  Suzuki‑Karasaki
    • Toyoko Ochiai
    • Chisei  Ra
  • View Affiliations

  • Published online on: May 17, 2012     https://doi.org/10.3892/ijo.2012.1483
  • Pages: 465-475
  • Copyright: © Suzuki et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is promising for cancer treatment owing to its selective cytotoxicity against malignant cells. However, some cancer cell types, including malignant melanoma cells, are resistant to TRAIL-induced apoptosis. Therefore, drugs that can amplify TRAIL cytotoxicity are urgently required. Depolarization of the plasma membrane potential is associated with apoptosis induced by a variety of death-inducing agents but its role in apoptosis remains a matter of debate. We found that TRAIL treatment resulted in robust depolarization in human melanoma cells with a considerable lag (2-4 h). Moreover, membrane-depolarizing agents, including K+ and ATP-sensitive K+ (KATP) channel inhibitors glibenclamide and U37883A enhanced TRAIL-induced apoptosis. On the contrary, inhibitors of calcium- and voltage-dependent K+ channels and mitochondrial KATP channels had no such effects. Melanocytes were insensitive to TRAIL-induced depolarization and apoptosis as well as to the sensitization by membrane-depolarizing agents despite their substantial surface expression of death receptors. TRAIL induced robust activation of X-box-binding protein-1 and caspase-12, both of which were enhanced by the K+ and KATP channel inhibitors, but not by other K+ channel inhibitors. Finally, caspase-12-selective inhibitor completely abolished the amplification of apoptosis. These findings suggest that depolarization promotes endoplasmic reticulum stress-mediated death pathway, thereby amplifying TRAIL cytotoxicity. Thus, membrane-depolarizing agents such as KATP channel inhibitors may have therapeutic potential in the treatment of TRAIL-resistant cancer cells without impairing tumor-selectivity.
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August 2012
Volume 41 Issue 2

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

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Spandidos Publications style
Suzuki Y, Inoue T, Murai M, Suzuki‑Karasaki M, Ochiai T and Ra C: Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K+ channels and endoplasmic reticulum stress. Int J Oncol 41: 465-475, 2012
APA
Suzuki, Y., Inoue, T., Murai, M., Suzuki‑Karasaki, M., Ochiai, T., & Ra, C. (2012). Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K+ channels and endoplasmic reticulum stress. International Journal of Oncology, 41, 465-475. https://doi.org/10.3892/ijo.2012.1483
MLA
Suzuki, Y., Inoue, T., Murai, M., Suzuki‑Karasaki, M., Ochiai, T., Ra, C."Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K+ channels and endoplasmic reticulum stress". International Journal of Oncology 41.2 (2012): 465-475.
Chicago
Suzuki, Y., Inoue, T., Murai, M., Suzuki‑Karasaki, M., Ochiai, T., Ra, C."Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K+ channels and endoplasmic reticulum stress". International Journal of Oncology 41, no. 2 (2012): 465-475. https://doi.org/10.3892/ijo.2012.1483