Biphasic Regulation of Mitogen-Activated Protein Kinase Phosphatase 3 in Hypoxic Colon Cancer Cells
| Autor: | Da Bin Kim, Myung-Shin Lee, Hong Seok Kim, Haeun Ko, Seung Ro Han, Jisu Lee, Yun Hee Kang, Seyoun Park |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
mitogen-activated protein kinase phosphatase 3 DUSP6 Transfection Mice Cell Line Tumor Tumor Microenvironment Animals Humans Protein kinase A Molecular Biology Tumor microenvironment biology Tumor hypoxia hypoxia-inducible factor-1α Kinase Chemistry hypoxia Cell Biology General Medicine Cell Hypoxia Cell biology colon cancer Tumor progression Cancer cell Colonic Neoplasms biology.protein MAPK phosphatase Mitogen-Activated Protein Kinase Phosphatases Research Article |
| Zdroj: | Molecules and Cells |
| ISSN: | 0219-1032 1016-8478 |
| Popis: | Hypoxia, or low oxygen tension, is a hallmark of the tumor microenvironment. The hypoxia-inducible factor-1α (HIF-1α) subunit plays a critical role in the adaptive cellular response of hypoxic tumor cells to low oxygen tension by activating gene-expression programs that control cancer cell metabolism, angiogenesis, and therapy resistance. Phosphorylation is involved in the stabilization and regulation of HIF-1α transcriptional activity. HIF-1α is activated by several factors, including the mitogen-activated protein kinase (MAPK) superfamily. MAPK phosphatase 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for extracellular signal-regulated kinase 1/2 (Erk1/2). Recent evidence indicates that hypoxia increases the endogenous levels of both MKP-3 mRNA and protein. However, its role in the response of cells to hypoxia is poorly understood. Herein, we demonstrated that small-interfering RNA (siRNA)-mediated knockdown of MKP-3 enhanced HIF-1α (not HIF-2α) levels. Conversely, MKP-3 overexpression suppressed HIF-1α (not HIF-2α) levels, as well as the expression levels of hypoxia-responsive genes (LDHA, CA9, GLUT-1, and VEGF), in hypoxic colon cancer cells. These findings indicated that MKP-3, induced by HIF-1α in hypoxia, negatively regulates HIF-1α protein levels and hypoxia-responsive genes. However, we also found that long-term hypoxia (>12 h) induced proteasomal degradation of MKP-3 in a lactic acid-dependent manner. Taken together, MKP-3 expression is modulated by the hypoxic conditions prevailing in colon cancer, and plays a role in cellular adaptation to tumor hypoxia and tumor progression. Thus, MKP-3 may serve as a potential therapeutic target for colon cancer treatment. |
| Databáze: | OpenAIRE |
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