TBOPP, a DOCK1 Inhibitor, Potentiates Cisplatin Efficacy in Breast Cancer by Regulating Twist-mediated EMT

Abstract

Background: DOCK1 has been reported to be involved in tumor progression and resistance. 1-(2-(30-(trifluoromethyl)-[1,10-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl2(1H)- pyridone (TBOPP) is a selective DOCK1 inhibitor; however, the role and molecular mechanisms of DOCK1 and its inhibition in breast cancer (BC) resistance remain poorly understood. Objective: This study aims toinvestigate the underlying mechanisms of DOCK1 in BC resistance. Methods: DOCK1 or Twist siRNA and Twist plasmid were used to explore the function of DOCK1 in vitro experiments. A mouse xenograft model was used for in vivo experiments. objective: In current study, we aimed to investigate the underlying mechanisms of DOCK1 in BC resistance. Results: In the present study, we demonstrated that DOCK1 siRNA promoted cisplatin sensitivity in BC cells. Moreover, TBOPP also enhances the therapeutic effect of cisplatin both in vitro and in vivo. Mechanistically, DOCK1 siRNA inhibited EMT. Twist 1 is one of the EMT-inducing transcription factors and is known to induce EMT. To further reveal the effect of DOCK in BC cells, we co-transfected with DOCK1 and Twist1 siRNA to BC cells and found that co-transfection with DOCK1 and Twist siRNA could not further enhance the cisplatin sensitivity of BC cells. Moreover, DOCK1 siRNA failed to reverse the effect of Twist 1 up-regulation. method: DOCK1 or Twist siRNA and Twist plasmid was used to explore the function of DOCK1 in vitro experiments. A mouse xenograft model was used for in vivo experiments. Conclusion: Taken together, these results demonstrate that DOCK1 may function as a potential therapeutic target in BC and that combining cisplatin with TBOPP may provide a promising therapeutic strategy for cisplatin-resistant BC patients.