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Amiloride potentiates TRAIL-induced tumor cell apoptosis by intracellular acidification-dependent Akt inactivation

Young-Lai Cho1, Kwang-Soon Lee, Seon-Jin Lee

  • 1Vascular System Research Center, Kangwon National University, Chunchon, Kangwon-do, Republic of Korea.

Biochemical and Biophysical Research Communications
|December 21, 2004
PubMed

Insights

Amiloride, a Na+/H+ exchanger inhibitor, enhances cancer cell apoptosis induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL). This occurs by promoting Akt dephosphorylation and caspase-8 activation, aiding TRAIL

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent.
  • TRAIL selectively induces apoptosis in tumor cells.
  • Resistance to TRAIL remains a challenge in cancer therapy.

Purpose of the Study:

  • To investigate if amiloride, a Na+/H+ exchanger inhibitor, enhances TRAIL-induced apoptosis in both sensitive and resistant tumor cells.
  • To elucidate the molecular mechanisms underlying amiloride's effect on TRAIL-induced apoptosis.

Main Methods:

  • Treatment of HeLa (sensitive) and LNCaP (resistant) cells with TRAIL and amiloride.
  • Assays for apoptosis, caspase-3 and -8 activation, cytochrome c release, and poly(ADP-ribose) polymerase (PARP) cleavage.
  • Measurement of intracellular pH and Akt phosphorylation levels.

Main Results:

  • Amiloride significantly enhanced TRAIL-induced apoptosis in both cell lines.
  • Amiloride increased the activation of caspase-3 and -8, cytochrome c release, and PARP cleavage.
  • Amiloride induced intracellular acidification and inhibited Akt phosphorylation.

Conclusions:

  • Amiloride sensitizes tumor cells to TRAIL-induced apoptosis by promoting Akt dephosphorylation and caspase-8 activation via intracellular acidification.
  • Na+/H+ exchanger inhibitors like amiloride may enhance TRAIL's anti-cancer activity, particularly in TRAIL-resistant tumors with high Akt activity.

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