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A Helical Polypeptide-Based Potassium Ionophore Induces Endoplasmic Reticulum Stress-Mediated Apoptosis by Perturbing
DaeYong Lee1, Soo-Hwan Lee2, Ilkoo Noh1
1Department of Chemical and Biomolecular Engineering Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141 Republic of Korea.
Abstract:
Perturbation of potassium homeostasis can affect various cell functions and lead to the onset of programmed cell death. Although ionophores have been intensively used as an ion homeostasis disturber, the mechanisms of cell death are unclear and the bioapplicability is limited. In this study, helical polypeptide-based potassium ionophores are developed to induce endoplasmic reticulum (ER) stress-mediated apoptosis. The polypeptide-based potassium ionophores disturb ion homeostasis and then induce prolonged ER stress in the cells. The ER stress results in oxidative environments that accelerate the activation of mitochondria-dependent apoptosis. Moreover, ER stress-mediated apoptosis is triggered in a tumor-bearing mouse model that suppresses tumor proliferation. This study provides the first evidence showing that helical polypeptide-based potassium ionophores trigger ER stress-mediated apoptosis by perturbation of potassium homeostasis.
Insights
New helical polypeptide-based potassium ionophores induce programmed cell death by disrupting cell ion balance and causing endoplasmic reticulum stress, offering a novel approach to cancer therapy.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Medicine
Background:
- Potassium homeostasis disruption can trigger programmed cell death.
- Current ionophores for disturbing ion homeostasis have unclear cell death mechanisms and limited applications.
Purpose of the Study:
- To develop helical polypeptide-based potassium ionophores.
- To investigate their mechanism in inducing endoplasmic reticulum (ER) stress-mediated apoptosis.
- To evaluate their efficacy in a tumor model.
Main Methods:
- Development of helical polypeptide-based potassium ionophores.
- Induction of ion homeostasis perturbation and prolonged ER stress in cells.
- Assessment of apoptosis activation via mitochondria-dependent pathways.
- Evaluation in a tumor-bearing mouse model.
Main Results:
- Polypeptide ionophores successfully disturbed potassium homeostasis, inducing prolonged ER stress.
- ER stress led to oxidative environments, accelerating mitochondria-dependent apoptosis.
- ER stress-mediated apoptosis was observed in a tumor model, suppressing tumor proliferation.
Conclusions:
- Helical polypeptide-based potassium ionophores effectively induce ER stress-mediated apoptosis.
- This mechanism involves the perturbation of potassium homeostasis.
- These ionophores show potential for suppressing tumor proliferation.
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