Inhibitory Effect of Interleukin-24 on Programmed Death Ligand 1 Expression via a Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2-Dependent Pathway in Human Triple-Negative Breast Cancer.
Background/Objectives: Programmed death ligand 1 (PD-L1) is often overexpressed in triple-negative breast cancer (TNBC), where it helps the tumor evade the immune system and promotes tumor growth. Interleukin-24 (IL-24) is recognized for its anti-tumor activity, although its role in immune regulation remains unclear. In this study, we examined the role of IL-24 in regulating PD-L1 and its anti-cancer activity in TNBC cells.
The study used TNBC cell lines treated with IL-24, delivered via a non-replicating adenovirus vector expressing the IL-24 gene. Assays included MTT for cell viability, Annexin V for apoptosis, Western blot for protein analysis, and qRT-PCR for mRNA analysis.
We found that the highly aggressive MDA-MB-231 cells had significantly higher PD-L1 levels. We discovered that treatment with IL-24 reduced cell growth, induced apoptosis, and significantly decreased PD-L1 protein levels in MDA-MB-231 cells. Mechanistically, we identified PKR, also known as eukaryotic translation initiation factor 2 alpha kinase 2, as a key mediator of IL-24-induced PD-L1 suppression. Additionally, doxorubicin, a primary chemotherapy drug used to treat triple-negative breast cancer, decreases PD-L1 expression and increases the sensitivity when combined with IL-24.
In this study, we show that IL-24 decreases PD-L1 expression in MDA-MB-231 cells through PKR activation, enhances the anti-tumor effects of Doxorubicin, and may enable lower doses that reduce toxicity and further decrease PD-L1 levels. These findings suggest that IL-24 could serve as a valuable target for therapeutic intervention and suggest that it can improve doxorubicin's effectiveness against aggressive breast cancer.
The study used TNBC cell lines treated with IL-24, delivered via a non-replicating adenovirus vector expressing the IL-24 gene. Assays included MTT for cell viability, Annexin V for apoptosis, Western blot for protein analysis, and qRT-PCR for mRNA analysis.
We found that the highly aggressive MDA-MB-231 cells had significantly higher PD-L1 levels. We discovered that treatment with IL-24 reduced cell growth, induced apoptosis, and significantly decreased PD-L1 protein levels in MDA-MB-231 cells. Mechanistically, we identified PKR, also known as eukaryotic translation initiation factor 2 alpha kinase 2, as a key mediator of IL-24-induced PD-L1 suppression. Additionally, doxorubicin, a primary chemotherapy drug used to treat triple-negative breast cancer, decreases PD-L1 expression and increases the sensitivity when combined with IL-24.
In this study, we show that IL-24 decreases PD-L1 expression in MDA-MB-231 cells through PKR activation, enhances the anti-tumor effects of Doxorubicin, and may enable lower doses that reduce toxicity and further decrease PD-L1 levels. These findings suggest that IL-24 could serve as a valuable target for therapeutic intervention and suggest that it can improve doxorubicin's effectiveness against aggressive breast cancer.
Authors
Smith Smith, Kim Kim, Sony Sony, Aslam Aslam, Torruella Torruella, de la Parra de la Parra, Sauane Sauane
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