Elevated 2-oxoglutarate antagonizes DNA damage responses in cholangiocarcinoma chemotherapy through regulating...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cholangiocarcinoma (CCA) exhibits resistance to conventional chemotherapy, often linked to DNA damage response (DDR) pathways.
• The role of 2-oxoglutarate (2-OG) dependent dioxygenases in DDR and their impact on CCA chemoresistance are not fully understood.

Purpose of the Study:

• To investigate the association between serum 2-OG levels and chemotherapy outcomes in CCA patients.
• To elucidate the mechanism by which 2-OG and aspartate beta-hydroxylase (ASPH) influence DDR and chemoresistance in CCA.

Main Methods:

• Serum 2-OG levels were measured in CCA patients before chemotherapy.
• CCA cell lines were treated with 2-OG, and ASPH expression was manipulated (overexpression and knockdown).
• The effects of targeting ASPH with small molecule inhibitors on chemotherapy response and DDR regulators (ATM, ATR) were assessed in vitro and in preclinical CCA models.

Main Results:

• Higher serum 2-OG levels were observed in CCA patients with progressive disease (PD) compared to those with stable disease (SD) or partial response (PR).
• Exogenous 2-OG and ASPH overexpression reduced DDR in CCA cells, while ASPH knockdown enhanced chemotherapy sensitivity.
• Targeting ASPH with inhibitors improved chemotherapy efficacy in CCA models by modulating ATM and ATR signaling.

Conclusions:

• Elevated 2-OG and ASPH contribute to CCA chemoresistance by antagonizing DDR pathways.
• Targeting ASPH presents a promising therapeutic strategy to enhance DNA damage responses and improve chemotherapy outcomes in cholangiocarcinoma.