Protein Kinase C Isoforms Differentially Regulate Hypoxia-Inducible Factor-1α Accumulation in Cancer Cells.
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.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, South Korea.
Hyunju
H
Kim
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, South Korea.
Yu-Ran
YR
Na
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, South Korea.|Department of Biomedical Engineering, Korea University of Science and Technology (UST), KIST campus, Seoul 136-791, South Korea.
So Yeon
SY
Kim
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, South Korea.|Department of Biological Chemistry, Korea University of Science and Technology (UST), KIST campus, Seoul 136-791, South Korea.
Eun Gyeong
EG
Yang
D015687:Cell Hypoxia; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D051571:Protein Kinase C-alpha / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; C497442:HIF1A protein, human; C546842:MTOR protein, human; C496628:PRKCA protein, human; C497258:PRKCD protein, human
HIF-1α; HYPOXIA; NF-κB; PKCα; PKCδ; mTOR