Aspirin Induces Mitochondrial Ca<sup>2+ </sup>Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca<sup>2+</sup> Entry
Aspirin (acetylsalicylic acid) and its metabolite salicylate, have an anti-melanoma effect by evoking mitochondrial dysfunction through poorly understood mechanisms. Depolarization of the plasma membrane potential leads to voltage-gated Ca<sup>2+</sup> entry (VGCE) and caspase-3 activati...
Main Authors: | , , , , , |
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Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-07-01
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Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/21/13/4771 |
Summary: | Aspirin (acetylsalicylic acid) and its metabolite salicylate, have an anti-melanoma effect by evoking mitochondrial dysfunction through poorly understood mechanisms. Depolarization of the plasma membrane potential leads to voltage-gated Ca<sup>2+</sup> entry (VGCE) and caspase-3 activation. In the present study, we investigated the role of depolarization and VGCE in aspirin’s anti-melanoma effect. Aspirin and to a lesser extent, salicylate (≥2.5 mM) induced a rapid (within seconds) depolarization, while they caused comparable levels of depolarization with a lag of 2~4 h. Reactive oxygen species (ROS) generation also occurred in the two-time points, and antioxidants abolished the early ROS generation and depolarization. At the same concentrations, the two drugs induced apoptotic and necrotic cell death in a caspase-independent manner, and antioxidants and Ca<sup>2+ </sup>channel blockers prevented cell death. Besides ROS generation, reduced mitochondrial Ca<sup>2+</sup> (Ca<sup>2+</sup><sub>m</sub>) and mitochondrial membrane potential preceded cell death. Moreover, the cells expressed the Ca<sub>v</sub>1.2 isoform of l-type Ca<sup>2+ </sup>channel, and knockdown of Ca<sub>v</sub>1.2 abolished the decrease in Ca<sup>2+</sup><sub>m</sub>. Our findings suggest that aspirin and salicylate induce Ca<sup>2+</sup><sub>m</sub> remodeling, mitochondrial dysfunction, and cell death via ROS-dependent depolarization and VGCE activation. |
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ISSN: | 1661-6596 1422-0067 |