12(S)-hydroxyeicosatetraenoic acid and 13(S)-hydroxyoctadecadienoic acid regulation of protein kinase C-α in melanoma cells: Role of receptor- mediated hydrolysis of inositol phospholipids

B. Liu, W. A. Khan, Y. A. Hannun, J. Timar, J. D. Taylor, S. Lundy, I. Butovich, K. V. Honn

Research output: Article

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Abstract

Protein kinase C (PKC) isoenzymes are essential components of cell signaling. In this study, we investigated the regulation of PKC-α in murine B16 amelanotic melanoma (B16a) cells by the monohydroxy fatty acids 12(S)- hydroxyeicosatetraenoic acid [12(S)-HETE] and 13(S)-hydroxyoctadecadienoic acid [13(S)-HODE]. 12(S)-HETE induced a translocation of PKC-α to the plasma membrane and focal adhesion plaques, leading to enhanced adhesion of B16a cells to the matrix protein fibronectin. However, 13(S)-HODE inhibited these 12(S)-HETE effects on PKC-α. A receptor-mediated mechanism of action for 12(S)-HETE and 13(S)-HODE is supported by the following findings. First, 12(S)-HETE triggered a rapid increase in cellular levels of diacylglycerol and inositol trisphosphate in B16a cells. 13(S)-HODE blocked the 12(S)-HETE- induced bursts of both second messengers. Second, the 12(S)-HETE-increased adhesion of B16a cells to fibronectin was sensitive to inhibition by a phospholipase C inhibitor and pertussis toxin. Finally, a high-affinity binding site (K(d) = 1 nM) for 12(S)-HETE was detected in B16a cells, and binding of 12(S)-HETE to B16a cells was effectively inhibited by 13(S)-HODE (IC50 = 4 nM). In summary, our data provide evidence that regulation of PKC-α by 12(S)-HETE and 13(S)-HODE may be through a guanine nucleotide- binding protein-linked receptor-mediated hydrolysis of inositol phospholipids.

Original languageEnglish
Pages (from-to)9323-9327
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number20
DOIs
Publication statusPublished - okt. 12 1995

ASJC Scopus subject areas

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