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PLOD3 contributes to HER-2 therapy resistance in gastric cancer through FoxO3/Survivin pathway

Yueda Chen1, Botian Ye2, Chunyan Wang3

  • 1Department of General Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, China.

Cell Death Discovery
|July 14, 2022
PubMed

Insights

Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3 (PLOD3) drives resistance to Trastuzumab therapy in HER-2 positive gastric cancer. Targeting the PLOD3-FoxO3-Survivin pathway may improve treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Human epidermal growth factor receptor 2 (HER-2) is a therapeutic target in breast and gastric cancers.
  • Resistance to HER-2 targeted therapies like Trastuzumab is a significant clinical challenge in gastric adenocarcinoma.
  • The underlying mechanisms of HER-2 therapy resistance in gastric cancer are not fully understood due to tumor heterogeneity.

Purpose of the Study:

  • To investigate the role of Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3 (PLOD3) in Trastuzumab resistance in gastric cancer.
  • To elucidate the molecular mechanisms by which PLOD3 contributes to therapy resistance.
  • To identify potential therapeutic targets for overcoming Trastuzumab resistance in HER-2 positive gastric cancer.

Main Methods:

  • Analysis of clinical gastric cancer samples and cell lines.
  • Depletion of PLOD3 in Trastuzumab-resistant gastric cancer cell lines.
  • Assessment of cell proliferation, tumor growth, and Trastuzumab sensitivity.
  • Investigation of the PLOD3-FoxO3-Survivin signaling axis.

Main Results:

  • PLOD3 expression is increased in Trastuzumab-resistant gastric cancer.
  • Depletion of PLOD3 reduces cell proliferation, tumor growth, and enhances Trastuzumab sensitivity.
  • Increased PLOD3 expression correlates with poor response to Trastuzumab therapy in patients.
  • PLOD3 represses tumor suppressor FoxO3, leading to increased Survivin, contributing to resistance.

Conclusions:

  • PLOD3 is a key mediator of Trastuzumab resistance in HER-2 positive gastric cancer.
  • The PLOD3-FoxO3-Survivin pathway represents a novel therapeutic target.
  • Targeting this pathway holds promise for improving treatment efficacy in gastric cancer patients.

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