Melittin Inhibits the Expression of Key Genes Involved in Tumor Microenvironment Formation by Suppressing HIF-1α Signaling in Breast Cancer Cells
| Autor: | Kazem Parivar, Latifeh Karimzadeh, Zabih Mir Hassani, Somayeh Abdirad, Mohammad Nabiuni |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Angiogenesis Antineoplastic Agents Breast Neoplasms complex mixtures Melittin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Gene expression Tumor Microenvironment Humans Cell Proliferation Tumor microenvironment Dose-Response Relationship Drug technology industry and agriculture Hematology General Medicine Hypoxia-Inducible Factor 1 alpha Subunit Melitten Cell biology Gene Expression Regulation Neoplastic Vascular endothelial growth factor A Oncology chemistry Apoptosis 030220 oncology & carcinogenesis Female lipids (amino acids peptides and proteins) Signal transduction Signal Transduction |
| DOI: | 10.21203/rs.3.rs-395664/v1 |
| Popis: | Purpose: HIF-1α has critical roles in formation of Tumor microenvironment by regulating genes involved in angiogenesis and anaerobic respiration. TME fuels tumors growth and metastasis and presents therapy with several challenges. Therefore, we aimed to investigate if Melittin disrupts HIF-1α signaling pathway in breast adenocarcinoma cell line MDA-MB-231.Methods: breast adenocarcinoma cell line MDA-MB-231 was cultured in presence of different doses of Melittin and MTT assay was carried out to measure Melittin’s cytotoxic. Cells were exposed to 5% C2 to mimic hypoxic conditions and Melittin. Western blot was used to measure HIF-1α protein levels. Gene expression analysis was performed using real-time PCR to measure relative mRNA abundance of genes involved in tumor microenvironment formation.Findings: Our results revealed that Melittin effectively inhibits HIF-1α at transcriptional and translation/post-translational level. HIF-1α protein and mRNA level was significantly decreased in Melittin-treated groups. It is found that inhibition of HIF-1α by Melittin is through downregulation of NFκB gene expression. Furthermore, gene expression analysis showed a downregulation in VEGFA and LDHA expression due to inhibition of HIF-1α protein by Melittin. In addition, cell toxicity assay showed that Melittin inhibits the growth of MDA-MB-231 cell line through activation of extrinsic and intrinsic apoptotic pathways by upregulating TNF and BAX expression. Conclusions: Melittin suppresses the expression of genes responsible for formation of TME physiological hallmarks by suppressing HIF-1α signaling pathway. Our results suggest that Melittin can modulate tumor microenvironment by inhibition of VEGFA and LDHA. |
| Databáze: | OpenAIRE |
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