RAC1 inhibition reverses cisplatin resistance in esophageal squamous cell carcinoma and induces downregulation of glycolytic enzymes

Abstract

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.

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

“…In esophageal squamous cell carcinoma, Rac1 expression was associated with poor prognosis and therapy resistance. Use of the Vav/Rac inhibitor EHop-016 was shown to overcome cisplatin resistance in esophageal squamous cell carcinoma in vitro and in vivo and by decreasing Akt/FOXO3a signaling and glycolysis (Schmit et al, 2019;Zeng et al, 2019), further validating its therapeutic applicability. Moreover, Tiam1 and Rac1 were overexpressed in a 3-D model of lymphoma, where treatment with Tiam1/Rac1 inhibitor NSC23766 overcame chemoresistance to doxorubicin (Ikram et al, 2018).…”

Targeting Rho GTPase Signaling Networks in Cancer

“…These include compounds that inhibit GEF-GTPase binding, which have produced promising results in preclinical cancer models. For example, EHop-016 blocks the interaction of Rac1 with Vav2 (Montalvo-Ortiz et al, 2012), and has been shown to enhance the anti-tumor effect of cisplatin in xenograft models of esophageal squamous cell carcinoma (Zeng et al, 2019). ZCL278 blocks the interaction of Cdc42 with intersectin (Friesland et al, 2013) and can inhibit the growth of lung cancer xenografts (Aguilar et al, 2019).…”

Alteration of plasma metabolites associated with chemoradiosensitivity in esophageal squamous cell carcinoma via untargeted metabolomics approach

“…And several key proteins in the glycolytic pathway have been discovered as promising targets for overcoming chemoresistance [ 39 – 41 ]. It was reported that suppressing glycolytic enzymes by inhibiting RAC1 showed reduced cisplatin resistance in esophageal squamous cell carcinoma [ 42 ]. Meanwhile, pretreatment whole-body total lesion glycolysis was uncovered as an independent predictor of outcomes in patients with esophageal cancer treated with definitive chemoradiotherapy [ 43 ].…”