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Open AccessArticle

Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells

1
Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
2
Health Administration Center, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
3
Department of Internal Medicine, Fujikawa Hospital, 1-2-6 Matsubara, Saga 840-0831, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(5), 1022; https://doi.org/10.3390/ijms20051022
Received: 30 January 2019 / Revised: 20 February 2019 / Accepted: 21 February 2019 / Published: 26 February 2019
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% O2) 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. View Full-Text
Keywords: Vitamin K2; Hypoxia-inducible factor-1α (HIF-1α); Protein kinase C (PKC); Hepatocellular carcinoma cells Vitamin K2; Hypoxia-inducible factor-1α (HIF-1α); Protein kinase C (PKC); Hepatocellular carcinoma cells
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Xia, J.; Ozaki, I.; Matsuhashi, S.; Kuwashiro, T.; Takahashi, H.; Anzai, K.; Mizuta, T. Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells. Int. J. Mol. Sci. 2019, 20, 1022.

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