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Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma

Yuko Kinowaki1, Morito Kurata1, Sachiko Ishibashi1

  • 1Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|February 22, 2018
PubMed

Insights

Glutathione peroxidase 4 (GPX4) overexpression predicts poor survival in diffuse large B-cell lymphoma. GPX4 regulates cell death, suggesting ferroptosis-based therapies and GPX4 as a prognostic marker for this cancer.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Oxidative stress and redox system regulation are critical in cancer development and progression.
  • Glutathione peroxidase 4 (GPX4), an antioxidant enzyme, plays a role in cell death by inhibiting membrane phospholipid peroxidation.
  • Limited research exists on GPX4 expression and clinical significance in malignant lymphomas, including diffuse large B-cell lymphoma (DLBCL).

Purpose of the Study:

  • To investigate the expression of GPX4 in diffuse large B-cell lymphoma (DLBCL).
  • To evaluate the clinical relevance of GPX4 expression as a prognostic predictor in DLBCL.
  • To explore the role of GPX4 in regulating cell death, particularly in response to reactive oxygen species (ROS).

Main Methods:

  • Immunohistochemical analysis was used to assess GPX4 expression in 93 DLBCL cases.
  • Correlation between GPX4 expression, 8-hydroxydeoxyguanosine (8-OHdG) levels (an oxidative stress marker), and patient survival (overall and progression-free) was analyzed.
  • In vitro studies were conducted to examine the effect of GPX4 overexpression and knockdown on cell death induced by reactive oxygen species.

Main Results:

  • GPX4 was expressed in 35.5% of DLBCL cases.
  • GPX4-positive DLBCL patients exhibited significantly poorer overall survival and progression-free survival compared to GPX4-negative patients.
  • A negative correlation was observed between GPX4 expression and 8-OHdG levels. GPX4-positive/8-OHdG-negative cases showed the worst prognosis.
  • GPX4 overexpression conferred resistance to ROS-induced cell death, while GPX4 knockdown sensitized cells to ROS-induced death.

Conclusions:

  • GPX4 overexpression is an independent prognostic predictor for poor outcomes in diffuse large B-cell lymphoma.
  • GPX4 plays a crucial role in regulating reactive oxygen species-induced cell death, potentially through ferroptosis.
  • These findings suggest GPX4 as a potential therapeutic target and prognostic biomarker for DLBCL.

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