Protein Kinase C Isoforms Differentially Regulate Hypoxia-Inducible Factor-1α Accumulation in Cancer Cells

ABSTRACT Hypoxia‐inducible factor‐1α (HIF‐1α) is one of the key transcription factors that mediate adaptation to hypoxia. Despite increasing evidence implicating the PKC family as potential modulators of HIF‐1α, the molecular mechanisms of PKC isoform‐dependent HIF‐1α activity under hypoxic conditions have not been systematically elucidated in cancer cell lines. Here, we collectively investigated how each isoform of the PKC family contributes to HIF‐1α accumulation in the human cervical cancer cell line HeLa. Among the abundant PKC isoforms, blockade of either PKCα or PKCδ was found to substantially reduce HIF‐1α accumulation and transcriptional activity in hypoxic cells. Knockdown of PKCδ resulted in a reduction of HIF‐1α mRNA levels, whereas the HIF‐1α mRNA level was unchanged regardless of PKCα knockdown. Upon searching for the downstream effectors of these kinases, we found that PKCα controls HIF‐1α translation via AKT‐mTOR under hypoxic conditions. On the other hand, one of the well‐known transcriptional regulation pathways of HIF‐1α, nuclear factor‐κB (NF‐κB) is identified as a downstream effector of PKCδ. Taken together, our findings provide insights into the roles of PKC isoforms as additional, discrete modulators of hypoxia‐stimulated HIF‐1α accumulation through different signaling pathways. J. Cell. Biochem. 117: 647–658, 2016. © 2015 Wiley Periodicals, Inc.