Li Yuan, Feng Yuqing, Chen Dan
Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, China.
Cancers (Basel). 2024 Dec 4;16(23):4060. doi: 10.3390/cancers16234060.
BACKGROUND/OBJECTIVES: Drug resistance poses a substantial clinical challenge in melanoma treatment, yet the underlying mechanism remains elusive. Here, we report the novel role of laminB1, a nuclear structure protein, in regulating the response of BRAF-mutated melanoma cells to vemurafenib.
Our analysis of clinical samples and existing databases highlights the tight correlation between the laminB1 expression level and melanoma progression and prognosis. Notably, we observe that laminB1 expression is upregulated when BRAF-mutated melanoma cells develop resistance to vemurafenib. The knockdown of laminB1 substantially increases the sensitivity of melanoma cells to vemurafenib. Furthermore, we found laminB1 suppression increases cell apoptosis via the escalation of DNA damage in a vemurafenib-dose-dependent manner. Conversely, protective cell autophagy is negatively regulated by laminB1 suppression. Interestingly, this distinct regulation pattern of apoptosis and autophagy by laminB1 cooperatively promotes the response of BRAF-mutated melanoma cells to vemurafenib.
Our findings unveil the potential of laminB1 as both a diagnosis marker and a therapeutic target of melanoma.
背景/目的：耐药性在黑色素瘤治疗中构成了重大的临床挑战，但其潜在机制仍不清楚。在此，我们报告了核结构蛋白层粘连蛋白B1（laminB1）在调节BRAF突变的黑色素瘤细胞对维莫非尼（vemurafenib）反应中的新作用。
我们对临床样本和现有数据库的分析突出了层粘连蛋白B1表达水平与黑色素瘤进展及预后之间的紧密相关性。值得注意的是，我们观察到当BRAF突变的黑色素瘤细胞对维莫非尼产生耐药性时，层粘连蛋白B1表达上调。敲低层粘连蛋白B1可显著增加黑色素瘤细胞对维莫非尼的敏感性。此外，我们发现层粘连蛋白B1的抑制通过以维莫非尼剂量依赖的方式加剧DNA损伤来增加细胞凋亡。相反，保护性细胞自噬受到层粘连蛋白B1抑制的负调控。有趣的是，层粘连蛋白B1对凋亡和自噬的这种独特调控模式协同促进了BRAF突变的黑色素瘤细胞对维莫非尼的反应。
我们的研究结果揭示了层粘连蛋白B1作为黑色素瘤诊断标志物和治疗靶点的潜力。
