Development of chemoresistance remains a major challenge in treating esophageal squamous cell carcinoma (ESCC) patients despite treatment advances. However, the role of RAC1 in chemoresistance of ESCC and the underlying mechanisms remain largely unknown. In this study, we found that higher levels of RAC1 expression were associated with poorer prognosis in ESCC patients. Enhanced RAC1 expression increased cell proliferation, migration, and chemoresistance in vitro. Combination therapy using RAC1 inhibitor EHop-016 and cisplatin significantly promoted cell viability inhibition, G2/M phase cycle arrest, and apoptosis when compared to each monotherapy. Mechanistically, glycolysis was significantly downregulated in the RAC1 inhibitor monotherapy group and the combination group via inhibiting AKT/FOXO3a signaling when compared to the control group. Moreover, the silencing of RAC1 inhibited AKT/FOXO3a signaling and cell glycolysis while the upregulation of RAC1 produced an opposite effect. In murine xenograft models, the tumor volume and the expression of glycolytic enzymes were significantly reduced in combination therapy when compared to each monotherapy group. Overall, our study demonstrates that targeting RAC1 with an inhibitor overcomes cisplatin resistance in ESCC by suppressing glycolytic enzymes, which provides a promising strategy for treatment of ESCC in clinical practice.

中文翻译：

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RAC1抑制可逆转食管鳞状细胞癌中的顺铂耐药性，并诱导糖酵解酶的下调。

尽管治疗进展，化学抗药性的发展仍然是治疗食道鳞状细胞癌（ESCC）患者的主要挑战。但是，RAC1在ESCC的化学抗性中的作用及其潜在机制仍然未知。在这项研究中，我们发现高水平的RAC1表达与ESCC患者预后较差有关。增强的RAC1表达增加了体外细胞的增殖，迁移和化学抗性。与每种单一疗法相比，使用RAC1抑制剂EHop-016和顺铂的联合疗法可显着促进细胞活力抑制，G2 / M期周期停滞和细胞凋亡。从机理上讲，与对照组相比，RAC1抑制剂单药治疗组和联合治疗组的糖酵解通过抑制AKT / FOXO3a信号而显着下调。此外，RAC1的沉默抑制了AKT / FOXO3a信号传导和细胞糖酵解，而RAC1的上调产生了相反的作用。在鼠异种移植模型中，与每个单一疗法组相比，联合疗法的肿瘤体积和糖酵解酶的表达均明显降低。总体而言，我们的研究表明，用抑制剂靶向RAC1可通过抑制糖酵解酶克服ESCC中的顺铂耐药性，这为临床实践中的ESCC治疗提供了有希望的策略。