HMGB1 induces radioresistance through PI3K/AKT/ATM pathway in esophageal squamous cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• High mobility group box 1 (HMGB1) is implicated in cancer progression.
• The PI3K/Akt/ATM signaling pathway plays a critical role in cell survival and radioresistance.
• Understanding the interplay between HMGB1 and this pathway is crucial for improving esophageal cancer treatment.

Purpose of the Study:

• To investigate the role of HMGB1 in the radio-sensitivity of esophageal cancer cells.
• To elucidate the involvement of the PI3K/Akt/ATM pathway in HMGB1-mediated radioresistance.
• To assess the therapeutic potential of targeting HMGB1 for enhancing radiotherapy outcomes.

Main Methods:

• Immunohistochemical staining for HMGB1 and p-ATM in patient biopsies.
• Western blot and RT-qPCR to analyze PI3K/Akt/ATM pathway components.
• In vitro studies using esophageal cancer cell lines with PI3K/Akt pathway inhibition (ly294002) or activation (IGF1).
• In vivo xenograft tumor models in nude mice to evaluate HMGB1's effect on radioresistance.

Main Results:

• High expression of HMGB1 and p-ATM in patients is associated with significantly lower survival rates.
• HMGB1 depletion, particularly combined with PI3K/Akt inhibition, significantly reduced cell proliferation and invasion.
• HMGB1 silencing promoted apoptosis and cell cycle arrest (G0/G1) in vitro and in vivo, especially post-radiation.
• IGF1 treatment reversed the effects of HMGB1 depletion, indicating pathway-dependent mechanisms.

Conclusions:

• High HMGB1 and p-ATM expression predicts a poor prognosis for esophageal cancer patients undergoing chemo-radiotherapy.
• Down-regulation of HMGB1 enhances esophageal cancer cell radio-sensitivity.
• Targeting HMGB1, potentially in conjunction with PI3K/Akt pathway inhibitors, represents a promising strategy to improve radiotherapy efficacy.