Esculetin inhibited PI3K/Akt/mTOR pathway and enhances anti-colorectal cancer activity via binding to ENO1

Jianing MaShulipan MulatMiaomiao ZhangNabi Xinhua^*Weiyi Zhang^*

• Xinjiang Medical University, Ürümqi, China

Introduction: Colorectal cancer (CRC) ranks as the third most prevalent malignant tumor worldwide and is the second leading cause of cancer-related mortality. At present, while its standard treatment consists of a combination of surgery and chemotherapy, metastasis and recurrence are generally associated with poor prognosis.Methods: Flow cytometry, Hoechst 33342 staining were employed to detect the changes of cell cycle and apoptosis in CRC cells. The molecular mechanisms of Esc's anti-tumor properties were elucidated through Network pharmacology, transcriptome sequencing technology, drug affinity responsive target stability (DARTS) and molecular docking. The in vivo anti-tumor effects of Esc using the xenograft mouse model.Results: In this study, Esculetin (Esc) exerted significant anti-proliferative effects across the CRC cell lines HCT116 and HT-29. Furthermore, Esc triggered cell death, arrested the HCT116 cell cycle at the S phase and the HT-29 cell cycle at the G0/G1 phase, inhibited the PI3K/Akt/mTOR signaling pathway, and promoted anti-CRC effects both in vitro and in vivo. Additional mechanistic investigations revealed that Esc bound to the ENO1 protein and altered its stability. Moreover, silencing ENO1 expression reversed the anti-CRC effect of Esc.Discussion: This study highlighted the effects of Esc against CRC, clarified that Esc inhibits the PI3K/Akt/mTOR signaling pathway and enhances the anti-CRC activity by binding to ENO1, suggesting that ENO1 may become a potential target for the treatment of CRC. It may strengthen the evidentiary foundation for developing novel anti-tumor agents with enhanced efficacy and reduced toxicity.