AI Article Synopsis

  • Chemotherapy for colorectal cancer (CRC) needs effective yet low-toxicity treatments, and cepharanthine (Cep) shows promise due to its anti-tumor effects.
  • The study investigates how Cep affects mitochondrial function and induces ferroptosis in CRC cells, revealing that it down-regulates TOM20 and TOM70 expression and disrupts the NRF2 signaling pathway, leading to increased oxidative stress and cell death.
  • The findings suggest that targeting TOM proteins and the NRF2 pathway through Cep could provide a new, innovative approach to treating colorectal cancer.

Article Abstract

Background: Chemotherapy for colorectal cancer (CRC) urgently needs low-toxicity and highly effective phytomedicine. Cepharanthine (Cep) shown to have multiple anti-tumor effects, including colorectal cancer, whose pivotal mechanisms are not fully understood. Herein, the present work aims to reveal the impact of Cep on the mitochondrial and anti-injury functions of CRC cells.

Methods: The TOM70/20 expression was screened by bioinformatic databases. SW480 cells were utilized as the colorectal cancer cell model. The expression of TOM70/20 and the downstream molecules were measured by western blots (WB). The ferroptosis was analyzed using Transmission electron microscopy (TEM), C11-BODIPY, PGSK, and DCFH-DA probes, wherein the detection was performed by flow cytometry and laser confocal microscopy. The anti-cancer efficacy was conducted by CCK-8 and Annexin-V/PI assay. The rescue experiments were carried out using Fer-1 and TOM70 plasmid transfection.

Results: Bioinformatic data identified TOM20 and TOM70 were highly expressed in colorectal cancer, which could be down-regulated by Cep. Further findings disclosed that Cep treatment destroyed the mitochondria and inactivated the NRF2 signaling pathway, an essential pathway for resistance to ferroptosis, thereby promoting reactive oxygen species (ROS) generation in CRC cells. As a result, prominent ferroptosis could be observed in CRC cells in response to Cep, which thereby led to the reduced cell viability of cancer cells. On the contrary, recovery of TOM70 dampened the Cep-elicited mitochondria damage, ferroptosis, and anti-cancer efficacy.

Conclusion: In summary, Cep-mediated TOM inhibition inactivates the NRF2 signaling pathway, thereby triggering ferroptosis and achieving an anti-colorectal cancer effect. The current study provides an innovative chemotherapeutic approach for colorectal cancer with phytomedicine.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11478973PMC
http://dx.doi.org/10.1007/s00432-024-05974-1DOI Listing

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