Acidosis of the tumor microenvironment is a characteristic of solid tumors such as malignant melanoma. Main causes of the extracellular acidification are metabolic alterations in cancer cells. While numerous studies showed that acidosis promotes tumor invasiveness, metastasis, and neoangiogenesis resulting in malignant progression, contrary data reported that acidosis induces cell apoptosis, inhibits cell proliferation, and mediates cell autophagy. Here, we show that low pH (pH 6.7) induces senescent/quiescent phenotype in melanoma cells after long-time treatment defined by induction of SA-ß-galactosidase, upregulation of p21, G1 /G0 cell cycle arrest, and reduction of proliferation. Moreover, we revealed that extracellular acidosis triggers the inhibition of eIF2α and subsequently the activation of ATF4 expression, a key component of the integrated stress response (ISR), indicating an acid-mediated translation reprogramming. Interestingly, we also demonstrated that acidosis represses microphthalmia-associated transcription factor (MITF) and activates the expression of the receptor tyrosine kinase AXL. This MITFlow /AXLhigh phenotype is correlated with drug resistance and therapeutic outcome in melanoma. Our results suggest that acidosis is an important microenvironmental factor triggering phenotypic plasticity and promoting tumor progression.

中文翻译：

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细胞外酸中毒触发人黑素瘤细胞中的衰老样表型。

肿瘤微环境的酸中毒是诸如恶性黑色素瘤的实体瘤的特征。细胞外酸化的主要原因是癌细胞的代谢改变。尽管大量研究表明酸中毒会促进肿瘤的侵袭，转移和新血管生成，从而导致恶性进展，但相反的数据报道酸中毒会诱导细胞凋亡，抑制细胞增殖并介导细胞自噬。在这里，我们显示低pH（pH 6.7）在长期治疗后诱导黑色素瘤细胞衰老/静止表型，这是由诱导SA-β-半乳糖苷酶，p21上调，G1 / G0细胞周期阻滞和增殖减少所定义的。此外，我们发现细胞外酸中毒会触发eIF2α的抑制作用，进而触发ATF4表达的激活，整合应激反应（ISR）的关键组成部分，表明酸介导的翻译重编程。有趣的是，我们还证明了酸中毒会抑制小眼症相关转录因子（MITF）并激活受体酪氨酸激酶AXL的表达。这种MITFlow / AXLhigh表型与黑色素瘤的耐药性和治疗效果相关。我们的结果表明，酸中毒是触发表型可塑性并促进肿瘤进展的重要微环境因素。这种MITFlow / AXLhigh表型与黑色素瘤的耐药性和治疗效果相关。我们的结果表明，酸中毒是触发表型可塑性并促进肿瘤进展的重要微环境因素。这种MITFlow / AXLhigh表型与黑色素瘤的耐药性和治疗效果相关。我们的结果表明，酸中毒是触发表型可塑性并促进肿瘤进展的重要微环境因素。