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Novel Protein Kinase C-Mediated Control of Orai1 Function in Invasive Melanoma

机译：新型蛋白激酶C介导的侵袭性黑色素瘤Orai1功能的控制。

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The incidence of malignant melanoma, a cancer of the melanocyte cell lineage, has nearly doubled in the past 20 years. Wnt5A, a key driver of melanoma invasiveness, induces Ca2+ signals. To understand how store-operated calcium entry (SOCE) contributes to Wnt5A-induced malignancy in melanoma models, we examined the expression and function of STIM1 and Orai1 in patient-derived malignant melanoma cells, previously characterized as either highly invasive (metastatic) or noninvasive. Using both fluorescence microscopy and electrophysiological approaches, we show that SOCE is greatly diminished in invasive melanoma compared to its level in noninvasive cell types. However, no loss of expression of any members of the STIM and Orai families was observed in invasive melanoma cells. Moreover, overexpressed wild-type STIM1 and Orai1 failed to restore SOCE in invasive melanoma cells, and we observed no defects in their localization before or after store depletion in any of the invasive cell lines. Importantly, however, we determined that SOCE was restored by inhibition of protein kinase C, a known downstream target of Wnt5A. Furthermore, coexpression of STIM1 with an Orai1 mutant insensitive to protein kinase C-mediated phosphorylation fully restored SOCE in invasive melanoma. These findings reveal a level of control for STIM/Orai function in invasive melanoma not previously reported.
机译：在过去20年中，恶性黑色素瘤（一种黑色素细胞谱系的癌症）的发病率几乎翻了一番。 Wnt5A是黑色素瘤侵袭的关键驱动因素，可诱导Ca 2 + 信号。为了了解在黑色素瘤模型中存储操作性钙进入（SOCE）如何促进Wnt5A诱导的恶性肿瘤，我们检查了STIM1和Orai1在患者来源的恶性黑色素瘤细胞中的表达和功能，该细胞以前被表征为高度侵袭性（转移性）或非侵袭性。使用荧光显微镜和电生理学方法，我们表明与非侵袭性细胞类型中的水平相比，侵袭性黑色素瘤中SOCE大大降低。但是，在侵袭性黑色素瘤细胞中未观察到STIM和Orai家族的任何成员表达的损失。此外，过表达的野生型STIM1和Orai1未能恢复侵入性黑色素瘤细胞中的SOCE，并且我们在任何侵入性细胞系中的存储耗尽之前或之后均未观察到它们的定位缺陷。但是重要的是，我们确定SOCE通过抑制蛋白激酶C（Wnt5A的已知下游靶标）得以恢复。此外，STIM1与蛋白激酶C介导的磷酸化不敏感的Orai1突变体的共表达完全恢复了侵袭性黑色素瘤中的SOCE。这些发现揭示了以前未报道的浸润性黑色素瘤中STIM / Orai功能的控制水平。

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