DNA damage response proteins synergistically affect the cancer prognosis and resistance

Area of Science:

• Oncology
• Systems Biology
• Molecular Biology

Background:

• Oxidative stress can induce cancer cell apoptosis, but resistance limits therapeutic efficacy.
• Mechanisms of cancer cell resistance to oxidative stress-induced apoptosis are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying cancer cell resistance to oxidative stress.
• To identify key networks and protein interactions involved in cancer progression and resistance.

Main Methods:

• Integrated analysis of big data, transcriptome, proteome, and network analysis across six cancer types.
• System biology approach to identify DNA damage response (DDR) protein networks.
• Validation using H2O2-induced oxidative stress and DDR inhibitors in human lung cancer cells.

Main Results:

• Identified system-level interactions between DDR proteins (repair, checkpoints, anti-apoptotic) linked to cancer progression.
• Discovered DDR hubs between G1-S and M phases associated with poor prognosis.
• Demonstrated that increased DDR network expression contributes to resistance under high oxidative stress.

Conclusions:

• The study highlights the critical role of DDR networks in mediating cancer cell resistance to oxidative stress.
• Targeting specific 'disease-causing networks' is essential for developing novel network pharmacology strategies.
• Findings provide insights for combating therapeutic resistance in cancer research.