Calcium is a ubiquitous intracellular second messenger, playing central roles in the regulation of several biological processes. Alterations in Ca²⁺ homeostasis and signaling are an important feature of tumor cells to acquire proliferative and survival advantages, which include structural and functional changes in storage capacity, channels, and pumps. Here, we investigated the differences in Ca²⁺ homeostasis in vemurafenib-responsive and non-responsive melanoma cells. Also, the expression of the Na⁺/Ca²⁺ exchanger (NCX) and the impact of its inhibition were studied. For this, it was used B-RAF^V600E and NRAS^Q61R-mutated human melanoma cells. The intracellular Ca²⁺ chelator BAPTA-AM decreased the viability of SK-MEL-147 but not of SK-MEL-19 and EGTA sensitized NRAS^Q61R-mutated cells to vemurafenib. These cells also presented a smaller response to thapsargin and ionomycin regarding the cytosolic Ca²⁺ levels in relation to SK-MEL-19, which was associated to an increased expression of NCX1, NO basal levels, and sensitivity to NCX inhibitors. These data highlight the differences between B-RAF^V600E and NRAS^Q61R-mutated melanoma cells in response to Ca²⁺ stimuli and point to the potential combination of clinically used chemotherapeutic drugs, including vemurafenib, with NCX inhibitors as a new therapeutic strategy to the treatment of melanoma.

钙是一种普遍存在的细胞内第二信使，在多种生物过程的调节中起着核心作用。Ca ²⁺稳态和信号传导的改变是肿瘤细胞获得增殖和存活优势的一个重要特征，包括存储容量、通道和泵的结构和功能变化。在这里，我们研究了vemurafenib 反应性和非反应性黑色素瘤细胞中 Ca ²⁺稳态的差异。此外，还研究了 Na ⁺ /Ca ²⁺交换剂 (NCX)的表达及其抑制的影响。为此，使用了 B-RAF ^V600E和 NRAS ^Q61R突变的人类黑色素瘤细胞。细胞内 Ca ²⁺螯合剂 BAPTA-AM 降低了 SK-MEL-147 的活力，但不会降低 SK-MEL-19 的活力，EGTA 使 NRAS ^Q61R突变的细胞对^威罗菲尼敏感。这些细胞还对与SK-MEL-19 相关的细胞溶质 Ca ²⁺水平表现出对毒素沙精和离子霉素的较小反应，这与 NCX1 表达增加、NO 基础水平和对 NCX 抑制剂的敏感性有关。这些数据突出了 B-RAF ^V600E和 NRAS ^Q61R突变的黑色素瘤细胞对 Ca ²⁺刺激作出反应的差异，并指出了临床使用的化疗药物（包括^威罗非尼）与 NCX 抑制剂的潜在组合作为治疗的新治疗策略黑色素瘤。