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Selenium modulates AR/IGF-1R/EGFR and TROP2 signaling pathways and improves anticancer efficacy in murine mammary
Chih-Hung Guo1, Shiou-Yue Wang1, Chieh-Han Chung2
1Micronutrition and Biomedical Nutrition Laboratories, Institute of Biomedical Nutrition, Hung-Kuang University, Taichung, Taiwan; Taiwan Nutraceutical Association, Taipei, Taiwan.
Abstract:
The micronutrient selenium (Se) has been shown to exert potential anticancer properties. This study aimed to evaluate the effects of Se (in Se yeast form) on the selenoproteins (SELENO), AR/IGF-1R/EGFR, PI3K/Akt/mTOR and Ras/Raf/ERK cascades, and immune checkpoint blockade in TNBC murine 4T1 cells. We also assessed the effects of combination treatment with chemotherapeutic doxorubicin and Se on trophoblast cell surface antigen 2 (TROP2) levels. Compared with the control groups, cells incubated with Se (0.25, 0.5, 0.75, 1.0, 1.5 µg Se/mL) have lower viability, raised intracellular Se concentrations and SELENO expression, and higher malondialdehyde products in a dose-dependent manner. Se induced the inactivation of AR/IGF-1R/EGFR and downregulation of the PI3K/Akt/mTOR and Ras/Raf/ERK signaling molecules. Se-treated cells also exhibited decreased mitochondrial membrane potential, reduced levels of the cell cycle regulatory protein cyclin D1, cancer stemness, metastatic and EMT-related markers, and increased apoptosis. Subsequently, Se treatment significantly suppressed PD-1/PD-L1 and CTLA-4 mRNA levels and proteins. Doxorubicin decreased 4T1 cell viability and TROP2 expression levels, but the addition of Se to doxorubicin contributed to further reductions. Similar responses to Se treatment were also observed in the human MDA-MB-231 and MCF-7 breast cancer cells. These results show that Se upregulates SELENO and anti-AR/IGF-1R/EGFR signaling in TNBC cells, thus inducing oxidative stress-dependent apoptosis and cell cycle arrest, stemness, EMT, and metastasis, as well as blocking the immune checkpoint molecules. TROP2 down-regulation with Se is also a potential anti-TNBC therapeutic target.
Insights
Selenium (Se) supplementation shows promise against triple-negative breast cancer (TNBC). It reduces cancer cell viability, inhibits key signaling pathways, and blocks immune checkpoints, offering a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Immunology
Background:
- Selenium (Se) exhibits potential anticancer properties.
- Triple-negative breast cancer (TNBC) remains a challenging malignancy with limited therapeutic options.
Purpose of the Study:
- To investigate the effects of selenium yeast on TNBC cells.
- To evaluate selenium's impact on specific signaling pathways and immune checkpoints.
- To assess combination therapy with doxorubicin and selenium.
Main Methods:
- In vitro studies using murine 4T1 and human breast cancer cell lines (MDA-MB-231, MCF-7).
- Treatment with varying doses of selenium yeast.
- Analysis of selenoprotein (SELENO) expression, signaling cascades (AR/IGF-1R/EGFR, PI3K/Akt/mTOR, Ras/Raf/ERK), oxidative stress markers, cell cycle proteins, stemness, metastasis, EMT markers, apoptosis, and immune checkpoint molecules (PD-1/PD-L1, CTLA-4).
- Combination treatment with doxorubicin and selenium, assessing TROP2 levels.
Main Results:
- Selenium increased intracellular Se concentrations and SELENO expression, inducing oxidative stress.
- Selenium inactivated AR/IGF-1R/EGFR signaling and downregulated PI3K/Akt/mTOR and Ras/Raf/ERK pathways.
- Selenium reduced cell viability, proliferation (cyclin D1), stemness, metastasis, EMT markers, and suppressed immune checkpoints (PD-1/PD-L1, CTLA-4).
- Selenium enhanced doxorubicin's efficacy in reducing viability and TROP2 expression.
Conclusions:
- Selenium upregulates SELENO and inhibits key pro-cancer signaling pathways in TNBC cells.
- Selenium induces apoptosis, cell cycle arrest, and reduces stemness, EMT, and metastasis.
- Selenium blocks immune checkpoint molecules and enhances chemotherapy effects.
- Selenium-mediated TROP2 downregulation presents a potential therapeutic target for TNBC.
