AMP-kinase inhibitor dorsomorphin reduces the proliferation and migration behavior of colorectal cancer cells by targeting the AKT/mTOR Pathway

Background and Aim : Colorectal cancer (CRC) is among the leading causes of cancer-related mortality, despite extensive efforts in the identification of new treatment options. Hence, there is a need for the development of novel agents with therapeutic potential in treatment of CRC. Dorsomorphin has demonstrated antiproliferative activity against different malignancies. Here we have investigated the pharmaceutical potential of dorsomorphin in two‐dimensional and three‐dimensional cell‐culture models of CRC. Methods : The anti-proliferative, anti-migratory, apoptotic activity and effect of this agent on cell cycle was evaluated by MTT assay, wound healing assay and Flow cytometry, respectively, while the expression of genes involved in Wnt/Pi3K pathways was assessed at mRNA and/or proteins by RT-PCR or Western blot.Results : Dorsomorphin inhibited CRC cell growth by modulating the cyclinD1, surviving and p-Akt. This agent was able to reduce the migratory behaviors of CRC cells, compared to control cells, through perturbation of E-cadherin. Also our data showed that dorsomorphin enhanced the percentage of the cells in sub‐G1 and induced apoptosis in both late/early stages, as detected by annexin V. Also the regulatory effect of dorsomorphin on oxidant/antioxidant balance was assessed by cellular reactive oxygen species (ROS) generation. In particular, this data showed that dorsomorphin markedly increased the ROS production in CRC cells. Conclusion : Our finding demonstrated that dorsomorphin antagonizes cell growth and migration, through perturbation of Akt/mTOR/Wnt pathways in CRC, supporting further-studies on the therapeutic potential of this novel anticancer agent in treatment of colorectal cancer.

کلیدواژه ها:

Colorectal cancer ، Dorsomorphin ، Wnt/PI3K/Akt ‐pathway