Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Cell Death Research

Background:

• Autophagy's role in tumor chemotherapy resistance is established, but its interplay with cell death remains unclear.
• Reactive oxygen species (ROS) can trigger either autophagy or cell death depending on concentration.
• p53 is implicated in cellular stress responses and potentially autophagy regulation.

Purpose of the Study:

• To investigate the mechanism by which the ERK inhibitor CC90003 affects colorectal cancer growth.
• To elucidate the relationship between CC90003-induced autophagy, cell death, ROS, and p53.
• To evaluate the therapeutic potential of CC90003, alone and in combination with chloroquine (CQ), in colorectal cancer models.

Main Methods:

• In vitro and in vivo experiments using colorectal cancer cell lines and a xenograft mouse model.
• Treatment with the ERK inhibitor CC90003, ROS inhibitors (NAC, SFN), p53 inhibitor (PFTα), and chloroquine (CQ).
• Assessment of cell death, autophagy induction, ROS levels, and p53 dependency.

Main Results:

• CC90003 suppressed colorectal cancer growth by inducing cell death.
• CC90003 induced ROS, which in turn activated p53-dependent protective autophagy.
• Inhibiting ROS or p53 enhanced CC90003-induced cell death.
• Combination therapy of CC90003 plus CQ showed superior efficacy in a xenograft mouse model compared to single treatments.

Conclusions:

• CC90003 targets ERK, simultaneously inducing cell death and p53/ROS-dependent protective autophagy in colorectal cancer.
• The findings reveal a novel mechanism linking ERK inhibition, ROS, p53, and autophagy in cancer.
• Targeting ERK offers a promising therapeutic strategy for colorectal cancer, potentially enhanced by combination therapies like CC90003 plus CQ.