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 translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells.
Highlights
Hypoxia is a common microenvironment observed in a broad range of diseases, solid tumors, including hepatocellular carcinoma (HCC) [1,2]
The protein kinase C (PKC) activator TPA induced three-fold greater HIF-1α activity under both normoxic and hypoxic conditions compared to the control
The ethanol did not show any significant effect on the activity, indicating that PKCs were involved in the HIF-1α activation and that vitamin K2 (VK2) might suppress the HIF-1α activity via the PKCs in Huh7 cells
Summary
Hypoxia is a common microenvironment observed in a broad range of diseases, solid tumors, including hepatocellular carcinoma (HCC) [1,2]. Higher-level eukaryotes have developed specialized factors and mechanisms to adapt to hypoxic conditions. Hypoxia-inducible factor 1 (HIF-1) plays critical roles in cellular and systemic oxygen maintenance and functions as a master transcription factor by binding to the hypoxia responsive element (HRE) of targeted genes, such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO) [3,4]. HIF-1 is a heterodimeric factor consisting of α and β subunits that share the same basic helix-loop-helix construction. The β subunit is expressed constitutively, while the α subunit shows remarkably varied expression and activity in response to the environment
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