2022 World Conference on Lung Cancer (ePosters)-EP16.04-029. Downregulation of PHLPP2 Induced by Radiation Promotes GPX4-mediated Ferroptosis Defense and Radioresistance in Lung Cancer

EP16.04-029. Downregulation of PHLPP2 Induced by Radiation Promotes GPX4-mediated Ferroptosis Defense and Radioresistance in Lung Cancer

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Radiotherapy (RT) is commonly used in non-small cell lung cancer (NSCLC) treatment, but radioresistance remains a challenge. Ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation, has been found to play a role in RT-induced cell death. However, the connection between ferroptosis dysregulation and radioresistance is not well understood. In this study, the functional interaction between ferroptosis induced by RT and PHLPP2 expression in NSCLC was investigated.<br /><br />The experiment used clonogenic survival assay to assess radiosensitization in NSCLC cell lines. Cell viability, protein alterations, and mRNA expression were measured using MTT assay, Western blotting, and qRT-PCR. Flow cytometry was used to assess lipid peroxidation. Knockdown and overexpression of PHLPP2 were achieved using lentivirus and retrovirus-mediated delivery in NSCLC cells.<br /><br />The results showed that RT treatment led to downregulation of PHLPP2 expression in NSCLC cell lines, along with increased GPX4 expression. Knockdown of PHLPP2 increased clonogenic cell survival, proliferation, and decreased radiotherapy-induced lipid ROS production and PTGS2 mRNA expression. On the other hand, overexpression of PHLPP2 promoted cell death induced by GPX4 inhibitors/radiotherapy, and increased lipid ROS production and PTGS2 mRNA expression. The study suggests that PHLPP2 promotes RT-induced cell death by repressing GPX4 expression.<br /><br />The study identifies PHLPP2 as a critical regulator of ferroptotic cancer cell death and suggests that targeting PHLPP2, in combination with GPX4 inhibition, can trigger ferroptosis induced by radiotherapy. These findings provide insights into the mechanisms underlying radioresistance in NSCLC and may have implications for developing new treatments for lung cancer.

Asset Subtitle

Haihua Yang

Meta Tag

Speaker Haihua Yang

Topic Tumour Biology and Biomarkers - Tumour Biology & Preclinical Studies

Keywords

Radiotherapy

Non-small cell lung cancer

NSCLC treatment

Radioresistance

Ferroptosis

Cell death

Iron-dependent lipid peroxidation

PHLPP2 expression

Clonogenic survival assay

Lentivirus and retrovirus-mediated delivery