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.

• Authors: Hyunju Kim, Yu-Ran Na, So Yeon Kim, Eun Gyeong Yang
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 117 Issue 3 Pg. 647-58 (Mar 2016) ISSN: 1097-4644 [Electronic] United States
• PMID: 26284819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Isoenzymes
• RNA, Messenger
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PRKCA protein, human
• PRKCD protein, human
• Protein Kinase C-alpha
• Protein Kinase C-delta

Topics

• Cell Hypoxia
• Gene Expression Regulation, Neoplastic
• HeLa Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Isoenzymes (physiology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Biosynthesis
• Protein Kinase C-alpha (physiology)
• Protein Kinase C-delta (physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Stability
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)