Abstract
Calcium signaling plays important roles in physiological and pathological conditions, including cutaneous melanoma, the most lethal type of skin cancer. Intracellular calcium concentration ([Ca2+]i), cell membrane calcium channels, calcium related proteins (S100 family, E-cadherin, and calpain), and Wnt/Ca2+ pathways are related to melanogenesis and melanoma tumorigenesis and progression. Calcium signaling influences the melanoma microenvironment, including immune cells, extracellular matrix (ECM), the vascular network, and chemical and physical surroundings. Other ionic channels, such as sodium and potassium channels, are engaged in calcium-mediated pathways in melanoma. Calcium signaling serves as a promising pharmacological target in melanoma treatment, and its dysregulation might serve as a marker for melanoma prediction. We documented calcium-dependent endoplasmic reticulum (ER) stress and mitochondria dysfunction, by targeting calcium channels and influencing [Ca2+]i and calcium homeostasis, and attenuated drug resistance in melanoma management.
Highlights
Cutaneous melanoma, one of the most malignant skin cancers, emerges from pigmented melanocytes
N-methyl-D-aspartate receptor (NMDAR) calcium channel function is weak in melanoma cells but strongly contributes to cell proliferation and invasion when its encoding gene GRIN2A is mutated at certain sites, such as G762E, with less glutamate supplementation [34]
Overexpression of receptor for advanced glycation end products (RAGE) induced melanoma cells to become more metastatic by triggering cells into mesenchymal-like morphologies, which is associated with the upregulation of its ligand S100B, a calcium-binding protein [46]
Summary
One of the most malignant skin cancers, emerges from pigmented melanocytes. Calcium channels are widely expressed on several biological membranes, such as the mitochondrial, endoplasmic reticulum (ER), and plasma membranes. These channels regulate calcium flux and concentration under normal physiological conditions. Glutamate receptormediated calcium channels, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate receptor (NMDAR), and metabotropic glutamate receptors (mGluRs), are ROCCs and have been widely studied in nerve cells [3] Their roles have been described in other cell types, including melanoma. Opening andCa release the Ca2+ into the Figure channels onon thethe membranes of of plasma, mitochondria, and thethe endoplasmic reticFigure1.1.Calcium. Mitochondria, and endoplasmic ulum [14]. Mitochondria, and endoplasmic ulum [14]. [14]
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