Role of protein kinase Cδ in transmitting hypoxia signal to HSF and HIF‐1

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Abstract
An hypoxic microenvironment is an important modulator of gene expression in many pathophysiological conditions. In this study, we show a coordinate activation of heat shock transcription factor (HSF) and hypoxia‐inducible factor‐1 (HIF‐1) in RIF tumor cells by hypoxia. Since heat shock protein (hsp) and angiogenic factor genes that are regulated by HSF and HIF‐1 are thought to contribute to the malignant progression of hypoxic tumor cells, it was of our major interest to identify the components that are responsible for the activation of both HSF and HIF‐1. Our finding that a bioflavonoid quercetin (QCT), a well known inhibitor of hsp gene expression, significantly inhibited the transcriptional activation of HSF and HIF‐1 strongly suggests that QCT‐sensitive molecule(s) is involved in the transcriptional activation of HSF and HIF‐1 by hypoxia. Our results revealed that PCKα, δ and ϵ isoforms are expressed in RIF cells, but only PKCδ was specifically translocated to the membrane by hypoxia. Our results also revealed that the translocation of PKCδ was completely abrogated by QCT. Moreover, inhibiting the PKCδ activation, either pharmacologically with phorbol 12‐myristate 13‐acetate or with bisindolymaleimide II or genetically by transient transfection of a dominant negative PKCδ, significantly inhibited the transcriptional activation of HSF and HIF‐1 by hypoxia. These results strongly substantiate a view that the PKCδ isozyme is the QCT‐sensitive molecule that plays an important role in transmitting hypoxia signals to both HSF and HIF‐1. Here we show that the membrane translocation of PKCδ is dependent on the activation of phosphoinositol 3‐kinase (PI3K). Treatment with PI3K inhibitor, wortmannin or LY294002, abrogated not only PKCδ translocation but the subsequent transcriptional activation of HSF and HIF‐1 by hypoxia. Together, our study shows that the PKCδ isozyme acts as a shared component in transmitting hypoxia‐induced signals to both HSF and HIF‐1, and that the upstream regulator of PKCδ is PI3K.