SERPINE2/PN-1 regulates the DNA damage response and radioresistance by activating ATM in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy Research

Background:

• The DNA damage response (DDR) influences lung cancer radioresistance, but its regulators remain unclear.
• Understanding DDR mechanisms is crucial for improving lung cancer treatment efficacy.

Purpose of the Study:

• To identify novel regulators of the DDR and radiosensitivity in lung cancer.
• To elucidate the functional and mechanistic roles of SERPINE2 in lung cancer radioresistance.

Main Methods:

• Investigated SERPINE2 expression in radioresistant lung cancer cells.
• Utilized in vitro and in vivo models to assess the effect of SERPINE2 knockdown on radiosensitivity.
• Analyzed DNA repair pathways, including homologous recombination (HR) and cell cycle checkpoint recovery.
• Examined protein interactions (SERPINE2, MRE11, ATM, RAD51) and phosphorylation events.
• Correlated SERPINE2 expression and serum levels with patient prognosis and radiotherapy response.

Main Results:

• SERPINE2 is upregulated in radioresistant lung cancer cells and its knockdown enhances radiosensitivity.
• SERPINE2 deficiency impairs homologous recombination repair, accelerates cell cycle checkpoint recovery, and suppresses metastasis.
• SERPINE2 knockdown reduces p-ATM and RAD51 accumulation, crucial for DNA repair.
• SERPINE2 directly interacts with MRE11 and ATM, facilitating ATM phosphorylation in HR-mediated double-strand break repair.
• High SERPINE2 expression predicts poor prognosis in lung adenocarcinoma and poor radiotherapy response in NSCLC.

Conclusions:

• SERPINE2 is a novel modulator of the DNA damage response and radioresistance in lung cancer.
• Targeting SERPINE2 may represent a therapeutic strategy to overcome radioresistance in lung cancer patients.