Selenium in the treatment of colon cancer: Investigation of effect on epithelial mesenchymal transition
Öz
Aim: This study aimed to investigate the therapeutic effect of seleno-L-methionine (SLM), a selenium (Se) compound, on colorectal cancer (CRC) cells through epithelial-mesenchymal transition (EMT)-related transcription factors (ZEB1 and ZEB2).
Materials and Methods: The human colon carcinoma cell line (Caco-2) was treated with different concentrations of SLM (15.6–250 nmol/L) for 24 hours. Cell viability was assessed using the MTT assay, live/dead rate and morphology were evaluated by Calcein-AM/Propidium Iodide staining, and ZEB1 and ZEB2 gene expressions were analyzed by qRT-PCR.
Results: SLM decreased cell viability in a dose-dependent manner (IC50: 31.25 nmol/L). Live/dead analysis revealed a significant increase in non-viable cells in the SLM-treated group compared to controls, although clear apoptotic morphology was not consistently observed. qRT-PCR analysis revealed a significant downregulation of ZEB2 and a slight reduction in ZEB1 expression.
Conclusion: SLM exhibited cytotoxic effects and modulated EMT-related gene expression, suggesting potential therapeutic implications in CRC.
Anahtar Kelimeler
Colon cancer Selenium Epithelial-to-mesenchymal transition ZEB 1 ZEB 2 Cell viability
Etik Beyan
No data were obtained from animal or human experiments for this article. The study does not require ethics committee approval since it does not involve any human or animal subject.
Destekleyen Kurum
This study was not funded by any project. However, the use of certain equipment was supported by TÜBİTAK-supported project number TÜBİTAK-20AG031.
Proje Numarası
The authors report no funding or project
Teşekkür
Not applicable.
Kaynakça
- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2024;74(3):229-263.
- Zeineddine FA, Zeineddine MA, Yousef A, et al. Survival improvement for patients with metastatic colorectal cancer over twenty years. NPJ Precision Oncology. 2023;7(1):16.
- Kumar A, Gautam V, Sandhu A, Rawat K, Sharma A, Saha L. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. World Journal of Gastrointestinal Surgery. 2023;15(4):495.
- Filip S, Vymetalkova V, Petera J, et al. Distant metastasis in colorectal cancer patients—do we have new predicting clinicopathological and molecular biomarkers? A comprehensive review. International journal of molecular sciences. 2020;21(15):5255.
- Lu J, Kornmann M, Traub B. Role of epithelial to mesenchymal transition in colorectal cancer. International Journal of Molecular Sciences. 2023;24(19):14815.
- Yang J, Antin P, Berx G, et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nature reviews Molecular cell biology. 2020;21(6):341-352.
- Li M-Z, Wang J-J, Yang S-B, et al. ZEB2 promotes tumor metastasis and correlates with poor prognosis of human colorectal cancer. American journal of translational research. 2017;9(6):2838.
- Sreekumar R, Harris S, Moutasim K, et al. Assessment of nuclear ZEB2 as a biomarker for colorectal cancer outcome and TNM risk stratification. JAMA network open. 2018;1(6):e183115-e183115.
- Ali MS, Hussein RM, Kandeil MA. The pro-oxidant, apoptotic and anti-angiogenic effects of selenium supplementation on colorectal tumors induced by 1, 2-dimethylhydrazine in BALB/C mice. Reports of Biochemistry & Molecular Biology. 2019;8(3):216.
- Peters U, Takata Y. Selenium and the prevention of prostate and colorectal cancer. Molecular nutrition & food research. 2008;52(11):1261-1272.
- Spyridopoulou K, Aindelis G, Pappa A, Chlichlia K. Anticancer activity of biogenic selenium nanoparticles: apoptotic and immunogenic cell death markers in colon cancer cells. Cancers. 2021;13(21):5335.
- Connelly-Frost A, Poole C, Satia JA, Kupper LL, Millikan RC, Sandler RS. Selenium, folate, and colon cancer. Nutrition and cancer. 2009;61(2):165-178.
- Garbo S, Di Giacomo S, Łażewska D, et al. Selenium-containing agents acting on cancer—a new hope? Pharmaceutics. 2022;15(1):104.
- Risbud MV, Karamuk E, Moser R, Mayer J. Hydrogel-coated textile scaffolds as three-dimensional growth support for human umbilical vein endothelial cells (HUVECs): possibilities as coculture system in liver tissue engineering. Cell Transplantation. 2002;11(4):369-377.
- Jodynis-Liebert J, Kujawska M. Biphasic dose-response induced by phytochemicals: experimental evidence. Journal of Clinical Medicine. 2020;9(3):718.
- Nweke CO, Ogbonna CJ. Statistical models for biphasic dose-response relationships (hormesis) in toxicological studies. Ecotoxicology and Environmental contamination. 2017;12(1):39-55.
- Kuršvietienė L, Mongirdienė A, Bernatonienė J, Šulinskienė J, Stanevičienė I. Selenium anticancer properties and impact on cellular redox status. Antioxidants. 2020;9(1):80.
- Kim SJ, Choi MC, Park JM, Chung AS. Antitumor effects of selenium. International Journal of Molecular Sciences. 2021;22(21):11844.
- Zhu Y, Pu Q, Zhang Q, et al. Selenium‐binding protein 1 inhibits malignant progression and induces apoptosis via distinct mechanisms in non‐small cell lung cancer. Cancer medicine. 2023;12(16):17149-17170.
- Hu X-m, Li Z-x, Lin R-h, et al. Guidelines for regulated cell death assays: a systematic summary, a categorical comparison, a prospective. Frontiers in cell and developmental biology. 2021;9:634690.
- Wolf P, Schoeniger A, Edlich F. Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2022;1869(10):119317.
- Pal A, Dhar A, Shamim MA, et al. Selenium levels in colorectal cancer: A Systematic Review and Meta-Analysis of serum, plasma, and colorectal specimens. Journal of Trace Elements in Medicine and Biology. 2024:127429.
- Cheng Z, Yu S, He W, et al. Selenite induces cell cycle arrest and apoptosis via reactive oxygen species-dependent inhibition of the AKT/mTOR pathway in thyroid cancer. Frontiers in Oncology. 2021;11:668424.
- Lv C, Zeng Q, Qi L, et al. Sodium Selenite Induces Autophagy and Apoptosis in Cervical Cancer Cells via Mitochondrial ROS-Activated AMPK/mTOR/FOXO3a Pathway. Antioxidants. 2024;13(8):1004.
- Fan C-d, Fu X-y, Zhang Z-y, et al. Selenocysteine induces apoptosis in human glioma cells: evidence for TrxR1-targeted inhibition and signaling crosstalk. Scientific Reports. 2017;7(1):6465.
- Wiles ET, Bell R, Thomas D, Beckerle M, Lessnick SL. ZEB2 represses the epithelial phenotype and facilitates metastasis in Ewing sarcoma. Genes & cancer. 2013;4(11-12):486-500.
- Lu W, Kang Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Developmental cell. 2019;49(3):361-374.
- Kok DE, Kiemeney LA, Verhaegh GW, et al. A short-term intervention with selenium affects expression of genes implicated in the epithelial-to-mesenchymal transition in the prostate. Oncotarget. 2017;8(6):10565.
- Kaya DE, Göktürk F, Batırbek F, Arıkoğlu H. Investigation of the Effects of Juglone-Selenium Treatments on Epithelial-Mesenchimal Transition and Migration in BxPC-3 and PANC-1 Human Pancreatic Cancer Cells. Medical Journal of Bakirkoy. 2023;19(3).
Öz
Amaç: Bu çalışma, bir selenyum bileşiği olan seleno-L-metiyoninin (SLM), kolorektal kanser (KRK) hücrelerinde epitel-mezenkimal geçiş (EMT) ile ilişkili transkripsiyon faktörleri ZEB1 ve ZEB2 üzerindeki terapötik potansiyelini araştırmayı amaçlamıştır.
Gereç ve Yöntem: İnsan kolon karsinomu hücre hattı (Caco-2) 24 saat boyunca farklı konsantrasyonlarda SLM (15,6-250 nmol/L) ile tedavi edildi. Hücre canlılığı MTT testi ile değerlendirildi, canlı/ölü oranı ve morfoloji kalsein-AM/propidyum iyodür boyama ile değerlendirildi ve ZEB1 ve ZEB2 gen ekspresyonları qRT-PCR ile analiz edildi.
Bulgular: SLM, hücre canlılığını doza bağımlı olarak azalttı (IC50: 31,25 nmol/L). Canlı/ölü boyama sonuçları, SLM uygulanan gruplarda anlamlı düzeyde artmış ölü hücre oranı gösterdi; ancak tipik apoptotik morfolojik özellikler tutarlı şekilde gözlemlenmedi. qRT-PCR analizi, ZEB2'nin önemli bir şekilde azaldığını ve ZEB1 ekspresyonunda hafif bir azalma olduğunu ortaya koydu.
Sonuç: SLM, Caco-2 hücrelerinde sitotoksik etkiler göstermiş ve EMT ile ilişkili gen ekspresyonunu modüle etmiştir. Bu bulgular, SLM’nin CRC’de terapötik potansiyele sahip olabileceğini düşündürmektedir.
Anahtar Kelimeler
Kolon kanseri Selenyum Epitelyal mezenkimal geçiş ZEB 1 ZEB 2 Hücre canlılığı
Etik Beyan
No data were obtained from animal or human experiments for this article. The study does not require ethics committee approval since it does not involve any human or animal subject.
Destekleyen Kurum
This study was not funded by any project. However, the use of certain equipment was supported by TÜBİTAK-supported project number TÜBİTAK-20AG031.
Proje Numarası
The authors report no funding or project
Teşekkür
Not applicable.
Kaynakça
- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2024;74(3):229-263.
- Zeineddine FA, Zeineddine MA, Yousef A, et al. Survival improvement for patients with metastatic colorectal cancer over twenty years. NPJ Precision Oncology. 2023;7(1):16.
- Kumar A, Gautam V, Sandhu A, Rawat K, Sharma A, Saha L. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. World Journal of Gastrointestinal Surgery. 2023;15(4):495.
- Filip S, Vymetalkova V, Petera J, et al. Distant metastasis in colorectal cancer patients—do we have new predicting clinicopathological and molecular biomarkers? A comprehensive review. International journal of molecular sciences. 2020;21(15):5255.
- Lu J, Kornmann M, Traub B. Role of epithelial to mesenchymal transition in colorectal cancer. International Journal of Molecular Sciences. 2023;24(19):14815.
- Yang J, Antin P, Berx G, et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nature reviews Molecular cell biology. 2020;21(6):341-352.
- Li M-Z, Wang J-J, Yang S-B, et al. ZEB2 promotes tumor metastasis and correlates with poor prognosis of human colorectal cancer. American journal of translational research. 2017;9(6):2838.
- Sreekumar R, Harris S, Moutasim K, et al. Assessment of nuclear ZEB2 as a biomarker for colorectal cancer outcome and TNM risk stratification. JAMA network open. 2018;1(6):e183115-e183115.
- Ali MS, Hussein RM, Kandeil MA. The pro-oxidant, apoptotic and anti-angiogenic effects of selenium supplementation on colorectal tumors induced by 1, 2-dimethylhydrazine in BALB/C mice. Reports of Biochemistry & Molecular Biology. 2019;8(3):216.
- Peters U, Takata Y. Selenium and the prevention of prostate and colorectal cancer. Molecular nutrition & food research. 2008;52(11):1261-1272.
- Spyridopoulou K, Aindelis G, Pappa A, Chlichlia K. Anticancer activity of biogenic selenium nanoparticles: apoptotic and immunogenic cell death markers in colon cancer cells. Cancers. 2021;13(21):5335.
- Connelly-Frost A, Poole C, Satia JA, Kupper LL, Millikan RC, Sandler RS. Selenium, folate, and colon cancer. Nutrition and cancer. 2009;61(2):165-178.
- Garbo S, Di Giacomo S, Łażewska D, et al. Selenium-containing agents acting on cancer—a new hope? Pharmaceutics. 2022;15(1):104.
- Risbud MV, Karamuk E, Moser R, Mayer J. Hydrogel-coated textile scaffolds as three-dimensional growth support for human umbilical vein endothelial cells (HUVECs): possibilities as coculture system in liver tissue engineering. Cell Transplantation. 2002;11(4):369-377.
- Jodynis-Liebert J, Kujawska M. Biphasic dose-response induced by phytochemicals: experimental evidence. Journal of Clinical Medicine. 2020;9(3):718.
- Nweke CO, Ogbonna CJ. Statistical models for biphasic dose-response relationships (hormesis) in toxicological studies. Ecotoxicology and Environmental contamination. 2017;12(1):39-55.
- Kuršvietienė L, Mongirdienė A, Bernatonienė J, Šulinskienė J, Stanevičienė I. Selenium anticancer properties and impact on cellular redox status. Antioxidants. 2020;9(1):80.
- Kim SJ, Choi MC, Park JM, Chung AS. Antitumor effects of selenium. International Journal of Molecular Sciences. 2021;22(21):11844.
- Zhu Y, Pu Q, Zhang Q, et al. Selenium‐binding protein 1 inhibits malignant progression and induces apoptosis via distinct mechanisms in non‐small cell lung cancer. Cancer medicine. 2023;12(16):17149-17170.
- Hu X-m, Li Z-x, Lin R-h, et al. Guidelines for regulated cell death assays: a systematic summary, a categorical comparison, a prospective. Frontiers in cell and developmental biology. 2021;9:634690.
- Wolf P, Schoeniger A, Edlich F. Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2022;1869(10):119317.
- Pal A, Dhar A, Shamim MA, et al. Selenium levels in colorectal cancer: A Systematic Review and Meta-Analysis of serum, plasma, and colorectal specimens. Journal of Trace Elements in Medicine and Biology. 2024:127429.
- Cheng Z, Yu S, He W, et al. Selenite induces cell cycle arrest and apoptosis via reactive oxygen species-dependent inhibition of the AKT/mTOR pathway in thyroid cancer. Frontiers in Oncology. 2021;11:668424.
- Lv C, Zeng Q, Qi L, et al. Sodium Selenite Induces Autophagy and Apoptosis in Cervical Cancer Cells via Mitochondrial ROS-Activated AMPK/mTOR/FOXO3a Pathway. Antioxidants. 2024;13(8):1004.
- Fan C-d, Fu X-y, Zhang Z-y, et al. Selenocysteine induces apoptosis in human glioma cells: evidence for TrxR1-targeted inhibition and signaling crosstalk. Scientific Reports. 2017;7(1):6465.
- Wiles ET, Bell R, Thomas D, Beckerle M, Lessnick SL. ZEB2 represses the epithelial phenotype and facilitates metastasis in Ewing sarcoma. Genes & cancer. 2013;4(11-12):486-500.
- Lu W, Kang Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Developmental cell. 2019;49(3):361-374.
- Kok DE, Kiemeney LA, Verhaegh GW, et al. A short-term intervention with selenium affects expression of genes implicated in the epithelial-to-mesenchymal transition in the prostate. Oncotarget. 2017;8(6):10565.
- Kaya DE, Göktürk F, Batırbek F, Arıkoğlu H. Investigation of the Effects of Juglone-Selenium Treatments on Epithelial-Mesenchimal Transition and Migration in BxPC-3 and PANC-1 Human Pancreatic Cancer Cells. Medical Journal of Bakirkoy. 2023;19(3).
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Moleküler Hedefler |
| Bölüm | Araştırma Makalesi |
| Yazarlar | |
| Proje Numarası | The authors report no funding or project |
| Yayımlanma Tarihi | 30 Ağustos 2025 |
| Gönderilme Tarihi | 9 Mayıs 2025 |
| Kabul Tarihi | 30 Temmuz 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 11 Sayı: 2 |
