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<p>Radiotherapy remains a valuable yet limited option for select colon cancer cases, with radioresistance representing a major clinical challenge. Lipidomics screening identified autotaxin (ATX), also known as ENPP2, as a key mediator of radiation-induced metabolic reprogramming. Radiation exposure upregulated ATX expression and its product lysophosphatidic acid (LPA), which activated the LPAR2-AKT signaling axis to support tumor cell survival. Pharmacological ATX inhibition with HA130 or genetic ATX knockdown enhanced radiosensitivity in vitro by suppressing proliferation and promoting apoptosis. In mouse models, both HA130 treatment and ATX knockdown significantly suppressed tumor growth and improved radiotherapy efficacy, as shown by reduced tumor volume, weight, and Ki67-positive cell counts. Clinically, elevated ATX-LPA pathway activity was associated with poor patient prognosis. These findings establish ATX as a promising therapeutic target for overcoming radioresistance in colon cancer, supporting the combination of ATX inhibition with radiotherapy to improve treatment outcomes.</p>

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Inhibition of autotaxin sensitizes colon cancer to radiation by suppressing LPAR2-AKT survival signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Yingnan Zhang,
  • Yuanyuan Chen,
  • Wenwen Guo,
  • Yaru Guo,
  • Shengcheng Yao,
  • Xiaojin Wu

摘要

Radiotherapy remains a valuable yet limited option for select colon cancer cases, with radioresistance representing a major clinical challenge. Lipidomics screening identified autotaxin (ATX), also known as ENPP2, as a key mediator of radiation-induced metabolic reprogramming. Radiation exposure upregulated ATX expression and its product lysophosphatidic acid (LPA), which activated the LPAR2-AKT signaling axis to support tumor cell survival. Pharmacological ATX inhibition with HA130 or genetic ATX knockdown enhanced radiosensitivity in vitro by suppressing proliferation and promoting apoptosis. In mouse models, both HA130 treatment and ATX knockdown significantly suppressed tumor growth and improved radiotherapy efficacy, as shown by reduced tumor volume, weight, and Ki67-positive cell counts. Clinically, elevated ATX-LPA pathway activity was associated with poor patient prognosis. These findings establish ATX as a promising therapeutic target for overcoming radioresistance in colon cancer, supporting the combination of ATX inhibition with radiotherapy to improve treatment outcomes.