Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells
Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation proces...
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MDPI AG
2019-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/20/5/1022 |
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| author | Jinghe Xia Iwata Ozaki Sachiko Matsuhashi Takuya Kuwashiro Hirokazu Takahashi Keizo Anzai Toshihiko Mizuta |
| author_facet | Jinghe Xia Iwata Ozaki Sachiko Matsuhashi Takuya Kuwashiro Hirokazu Takahashi Keizo Anzai Toshihiko Mizuta |
| author_sort | Jinghe Xia |
| collection | DOAJ |
| description | Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O<sub>2</sub>) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells. |
| first_indexed | 2024-04-12T07:43:57Z |
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| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T07:43:57Z |
| publishDate | 2019-02-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f54afddb18084502a727e92d5a9348782022-12-22T03:41:45ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-02-01205102210.3390/ijms20051022ijms20051022Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma CellsJinghe Xia0Iwata Ozaki1Sachiko Matsuhashi2Takuya Kuwashiro3Hirokazu Takahashi4Keizo Anzai5Toshihiko Mizuta6Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Fujikawa Hospital, 1-2-6 Matsubara, Saga 840-0831, JapanHypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O<sub>2</sub>) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells.https://www.mdpi.com/1422-0067/20/5/1022Vitamin K2Hypoxia-inducible factor-1α (HIF-1α)Protein kinase C (PKC)Hepatocellular carcinoma cells |
| spellingShingle | Jinghe Xia Iwata Ozaki Sachiko Matsuhashi Takuya Kuwashiro Hirokazu Takahashi Keizo Anzai Toshihiko Mizuta Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells International Journal of Molecular Sciences Vitamin K2 Hypoxia-inducible factor-1α (HIF-1α) Protein kinase C (PKC) Hepatocellular carcinoma cells |
| title | Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells |
| title_full | Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells |
| title_fullStr | Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells |
| title_full_unstemmed | Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells |
| title_short | Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells |
| title_sort | mechanisms of pkc mediated enhancement of hif 1α activity and its inhibition by vitamin k2 in hepatocellular carcinoma cells |
| topic | Vitamin K2 Hypoxia-inducible factor-1α (HIF-1α) Protein kinase C (PKC) Hepatocellular carcinoma cells |
| url | https://www.mdpi.com/1422-0067/20/5/1022 |
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