Xanthohumol targets the ERK1/2-Fra1 signaling axis to reduce cyclin D1 expression and inhibit non-small cell lung cancer

High expression of cyclin D1 has a crucial role in the maintenance of unlimited cell growth in human cancer cells. The present study indicated that cyclin D1 was overexpressed in human non-small cell lung cancer (NSCLC) tumor tissues and cell lines. Knockout of cyclin D1 suppressed NSCLC cell growth, colony formation and in vivo tumor growth. Of note, the natural product xanthohumol (Xanth) inhibited NSCLC cells via the downregulation of cyclin D1. A further mechanistic study revealed that Xanth suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1 (Fra1), which eventually inhibited the transcriptional activity of activator protein-1 and decreased the mRNA level of cyclin D1. Furthermore, suppression of ERK1/2 impaired Fra1 phosphorylation and enhanced Xanth-induced Fra1 ubiquitination and degradation. In addition, the S265D mutation compromised Xanth-induced Fra1 degradation. Finally, the in vivo anti-tumor effect of Xanth was validated in a xenograft mouse model. In summary, the present results indicated that targeting ERK1/2-Fra1-cyclin D1 signaling is a promising anti-tumor strategy for NSCLC treatment.

细胞周期蛋白D1的高表达在人类癌细胞的无限细胞生长维持中起着关键作用。本研究表明，细胞周期蛋白D1在人类非小细胞肺癌（NSCLC）肿瘤组织和细胞系中过度表达。细胞周期蛋白D1的敲除抑制了NSCLC细胞生长、集落形成以及体内肿瘤生长。值得注意的是，天然产物黄腐酚（Xanth）通过下调细胞周期蛋白D1抑制NSCLC细胞。进一步的机制研究显示，黄腐酚抑制ERK1/2信号通路并降低FOS相关抗原1（Fra1）的蛋白水平，最终抑制激活蛋白 - 1的转录活性并降低细胞周期蛋白D1的mRNA水平。此外，抑制ERK1/2会削弱Fra1的磷酸化，并增强黄腐酚诱导的Fra1泛素化和降解。另外，S265D突变会削弱黄腐酚诱导的Fra1降解。最后，黄腐酚的体内抗肿瘤效应在异种移植小鼠模型中得到验证。总之，本研究结果表明，靶向ERK1/2 - Fra1 - 细胞周期蛋白D1信号通路是一种有前景的非小细胞肺癌治疗抗肿瘤策略。