背景:皮肤鳞状细胞癌(cSCC)是最常见的皮肤癌之一,迫切需要有效的药物。Echinatin,一种从甘草植物中提取的天然化合物,已显示出有希望的抗肿瘤效果。然而,棘突苷在cSCC中的疗效和直接靶点仍不清楚.
目的:本研究系统研究了棘突素对cSCC的抗肿瘤作用及其机制。
方法:三种cSCC细胞系,异种移植模型,并使用紫外线诱导的cSCC小鼠模型来研究儿茶素的潜在保护作用。通过蛋白质组微阵列测定法评估了棘突素与谷胱甘肽S-转移酶mu3(GSTM3)之间以及棘突素与过氧化物酶2(PRDX2)之间的相互作用,下拉LC-MS/MS分析,表面等离子体共振,和分子对接。通过使用蛋白质印迹分析了GSTM3介导的棘突素活性的潜在机制,慢病毒感染和小干扰RNA(siRNA)转染。
结果:在这项研究中,我们发现棘突抑制cSCC细胞的增殖和迁移,但对原代人角质形成细胞无细胞毒性作用.此外,echinatin在体内显着抑制肿瘤生长。机械上,我们的数据显示,棘突素可以直接结合GSTM3和PRDX2。值得注意的是,echinatin通过促进其蛋白酶体降解来抑制GSTM3和PRDX2水平,这导致了ROS生产的中断。然后,我们发现棘突素通过抑制GSTM3增加线粒体ROS的产生。此外,echinatin通过抑制GSTM3介导的铁凋亡负调节(FNR)蛋白触发铁凋亡。此外,echinatin调节GSTM3介导的ROS/MAPK信号传导。
结论:棘皮苷具有良好的体内外抗肿瘤作用。此外,我们的研究结果表明,GSTM3和PRDX2可以作为棘突抑制素在cSCC中的可行靶标。因此,echinatin代表了通过靶向GSTM3介导的铁凋亡来治疗cSCC的新方法。
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers for which effective drugs are urgently needed. Echinatin, a natural compound extracted from Glycyrrhiza plants, has shown promising antitumour effects. However, the efficacy and the direct target of
echinatin in cSCC remain unclear.
OBJECTIVE: This study conducted a systematic investigation of the antitumour effects of echinatin on cSCC and the underlying mechanisms involved.
METHODS: Three cSCC cell lines, a xenograft model, and a UV-induced cSCC mouse model were used to investigate the potential protective effects of echinatin. The interactions between
echinatin and glutathione S-transferase mu3 (GSTM3) and between
echinatin and peroxiredoxin-2 (PRDX2) were evaluated by a proteome microarray assay, pull-down LC‒MS/MS analysis, surface plasmon resonance, and molecular docking. The potential mechanisms of GSTM3-mediated echinatin activity were analysed by using western blotting, lentivirus infection and small interfering RNA (siRNA) transfection.
RESULTS: In this study, we found that echinatin inhibited the proliferation and migration of cSCC cells but had no cytotoxic effect on primary human keratinocytes. Furthermore,
echinatin significantly inhibited tumour growth in vivo. Mechanistically, our data showed that
echinatin could directly bind to GSTM3 and PRDX2. Notably, echinatin inhibited GSTM3 and PRDX2 levels by promoting their proteasomal degradation, which led to the disruption of ROS production. We then revealed that echinatin increased mitochondrial ROS production by inhibiting GSTM3. Moreover, echinatin triggered ferroptosis by inhibiting GSTM3-mediated ferroptosis negative regulation (FNR) proteins. In addition,
echinatin regulated GSTM3-mediated ROS/MAPK signalling.
CONCLUSIONS: Echinatin has good antitumour effects both in vitro and in vivo. Moreover, our findings indicate that GSTM3 and PRDX2 could function as viable targets of echinatin in cSCC. Consequently, echinatin represents a novel treatment for cSCC through the targeting of GSTM3-mediated ferroptosis.