Zhai Zili, Yamauchi Takeshi, Sandoval Karenna, Villarreal Kira, Kwong Man Wai Charlotte, Swanson Emily J, Tan Aik Choon, Fujita Mayumi
Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Cells. 2025 Jun 17;14(12):913. doi: 10.3390/cells14120913.
Aldehyde dehydrogenase 2 (ALDH2) is a crucial detoxifying enzyme that eliminates toxic aldehydes. ALDH2 deficiency has been linked to various human diseases, including certain cancers. We have previously reported downregulation in human melanoma tissues. Here, we further investigated the biological significance of downregulation in this malignancy. Analysis of TCGA dataset revealed that low expression correlates with poorer survival in metastatic melanoma. Examination of human metastatic melanoma cell lines confirmed that most had downregulation (-low) compared to primary melanocytes. In contrast, a small subset of metastatic melanoma cell lines exhibited normal levels (-normal). CRISPR/Cas9-mediated knockout in -normal A375 cells promoted tumor growth and MAPK/ERK activation. Given the pivotal role of MAPK/ERK signaling in melanoma and cellular response to acetaldehyde, we compared A375 with -low SK-MEL-28 and 1205Lu cells. -low cells were intrinsically resistant to BRAF and MEK inhibitors, whereas A375 cells were not. However, A375 cells acquired resistance upon knockout. Furthermore, melanoma cells with acquired resistance to these inhibitors displayed further ALDH2 downregulation. Our findings indicate that downregulation contributes to melanoma progression and therapy resistance in -mutated human metastatic melanoma cells, highlighting ALDH2 as a potential prognostic marker and therapeutic target in metastatic melanoma.
乙醛脱氢酶2（ALDH2）是一种至关重要的解毒酶，可清除有毒醛类。ALDH2缺乏与多种人类疾病相关，包括某些癌症。我们之前报道过其在人类黑色素瘤组织中的表达下调。在此，我们进一步研究了其在这种恶性肿瘤中表达下调的生物学意义。对TCGA数据集的分析显示，低表达与转移性黑色素瘤患者较差的生存率相关。对人类转移性黑色素瘤细胞系的检测证实，与原代黑素细胞相比，大多数细胞系的表达下调（-低）。相比之下，一小部分转移性黑色素瘤细胞系表现出正常水平（-正常）。在-正常的A375细胞中，通过CRISPR/Cas9介导的基因敲除促进了肿瘤生长和MAPK/ERK激活。鉴于MAPK/ERK信号在黑色素瘤以及细胞对乙醛反应中的关键作用，我们将A375细胞与-低的SK-MEL-28和1205Lu细胞进行了比较。-低的细胞对BRAF和MEK抑制剂具有内在抗性，而A375细胞则没有。然而，A375细胞在基因敲除后获得了抗性。此外，对这些抑制剂产生抗性的黑色素瘤细胞显示出进一步的ALDH2下调。我们的研究结果表明，在-突变的人类转移性黑色素瘤细胞中，ALDH2下调促进了黑色素瘤进展和治疗抗性，凸显了ALDH2作为转移性黑色素瘤潜在预后标志物和治疗靶点的作用。
