Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca2+ 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 Ca2+ entry (VGCE) and caspase-3 activation. In the present stud...

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Bibliographic Details
Published in:International journal of molecular sciences 2020-07, Vol.21 (13), p.4771
Main Authors: Fujikawa, Itsuho, Ando, Takashi, Suzuki-Karasaki, Manami, Suzuki-Karasaki, Miki, Ochiai, Toyoko, Suzuki-Karasaki, Yoshihiro
Format: Article
Language:English
Subjects:
Acetylsalicylic acid
Activation
Antioxidants
Apoptosis
Aspirin
Calcium (mitochondrial)
Calcium channels (L-type)
Calcium channels (voltage-gated)
Calcium influx
Calcium ions
Cancer therapies
Caspase-3
Cell cycle
Cell death
Cell growth
Depolarization
Drug dosages
Flow cytometry
Homeostasis
Kinases
Medical prognosis
Melanoma
Membrane potential
Membranes
Metabolites
Metastasis
Mitochondria
Morphology
Nonsteroidal anti-inflammatory drugs
Reactive oxygen species
Salicylic acid
Skin
Tumor cells
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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 Ca2+ 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 Ca2+ channel blockers prevented cell death. Besides ROS generation, reduced mitochondrial Ca2+ (Ca2+m) and mitochondrial membrane potential preceded cell death. Moreover, the cells expressed the Cav1.2 isoform of l-type Ca2+ channel, and knockdown of Cav1.2 abolished the decrease in Ca2+m. Our findings suggest that aspirin and salicylate induce Ca2+m remodeling, mitochondrial dysfunction, and cell death via ROS-dependent depolarization and VGCE activation.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms21134771