ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Pharmacological activation of the p53 tumor suppressor is a promising cancer therapy strategy.
• Unpredictable cellular responses to activated p53 limit its clinical efficacy.
• Understanding the molecular mechanisms governing p53's biological outcomes is crucial.

Purpose of the Study:

• To elucidate mechanisms controlling p53-mediated outcomes in cancer cells.
• To develop strategies for converting p53-induced growth arrest into apoptosis.
• To identify novel therapeutic targets for p53-based cancer treatments.

Main Methods:

• Concurrent pharmacological activation of p53 and inhibition of thioredoxin reductase.
• Induction and manipulation of reactive oxygen species (ROS) levels.
• Analysis of c-Jun N-terminal kinase (JNK) activation, DNA damage response, and p53 feedback loops.
• Identification of oncogenes and p53 inhibitors regulated by p53 and JNK.

Main Results:

• Concurrent p53 activation and ROS generation induce synthetic lethality in cancer cells.
• ROS promote JNK activation and DNA damage response, creating a positive feedback loop with p53.
• This feedback loop shifts p53's effect from growth arrest to apoptosis.
• Several pro-survival oncogenes (Mcl1, PI3K, eIF4E) and p53 inhibitors (Wip1, MdmX) were identified as JNK-dependent targets of p53.
• Ablation of Wip1, a JNK downstream executor, enhanced and sustained p53 transcriptional activity, promoting cell death.

Conclusions:

• Concurrent p53 activation and ROS generation offer a novel strategy for cancer therapy.
• This approach converts p53-induced cell cycle arrest into apoptosis via a JNK-ROS-p53 feedback loop.
• Targeting ROS levels in conjunction with p53 reactivation can selectively eliminate cancer cells, particularly aggressive ones with high ROS levels.