The Role of Calcium Signaling in Melanoma

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.

The Modulation of Melanogenesis in B16 Cells Upon Treatment with Plant Extracts and Isolated Plant Compounds

“…Increased calcium levels activate TYR, resulting in melanin production. Therefore, ORAC channel antagonists play a key role in inhibiting UV-induced melanogenesis [ 167 , 168 ].…”

The sun, cholesterol and Orai1 conspire in melanoma

“…Several mutations have been associated with malignant transformation and metastatic progression, and the primary trigger is exposure to UV radiation (Zhang et al , 2022). Various components of the Ca 2+ signaling pathway are also implicated in malignant transformation, including Ca 2+ permeable channels, Ca 2+ pumps, Orai1, STIM2, and mitochondrial Ca 2+ uptake (Zhang et al , 2019, 2022). However, the role of Ca 2+ influx in UV radiation‐triggered malignant transformation is not well‐defined.…”

“…Ca 2+ influx by the STIM1‐activated Orai1 generally promotes cancer via its role in cell transformation and tumor progression (Hammad & Machaca, 2021). In melanoma, a malignancy of pigment‐producing skin cells, the Orai and STIM proteins regulate cells within the tumor environment and control the integrity of the extracellular matrix to facilitate metastasis (Zhang et al , 2022). Melanoma is characterized by progressive phases in which melanocytes first become hyperplastic, then transform into melanoma in situ , and finally progress to highly proliferative and invasive cells, culminating in fatal metastasis.…”

Store-operated calcium channels in skin

“…The role of STIM1 and Orai1 in melanocyte biology has been detailed by relatively few studies, which may be explained by the fact that melanocyte research is often linked to the goal of understanding melanoma pathology (reviewed by Stanisz et al, 2016 and Zhang et al, 2022 ). Studies have reported differing Orai1-3 and STIM1-2 expression profiles across model systems, and although STIM2 expression often exceeds that of STIM1, it appears to be STIM1 that activates Orai channels and AC6 in melanocytes ( Stanisz et al, 2012 , 2014 ; Motiani et al, 2018 ).…”