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

International Journal of Molecular Sciences
Jinghe XiaToshihiko Mizuta

Abstract

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 transloc...Continue Reading

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Citations

Jan 22, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sylwia MachcinskaBarbara Gawronska-Kozak
Mar 2, 2021·Acta Pharmaceutica Sinica. B·Yifan ChenMeidan Ying
May 29, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Hui-Yao LiXin-Yuan Gao
Dec 6, 2020·Clinical Nutrition : Official Journal of the European Society of Parenteral and Enteral Nutrition·Kang WangGuosheng Ren
May 27, 2021·Antioxidants & Redox Signaling·Amaya Lopez-PascualPedro González-Muniesa

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Methods Mentioned

BETA
ubiquitination
ChIP
Nuclear
nuclear translocation
protein assay
PCR
Immunoprecipitation

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