The mechanism of skin tumor promotion caused by phorbol esters: Possible involvement of arachidonic acid cascade/lipoxygenase, protein kinase C and calcium/calmodulin systems.

Recombinant human interleukin-1β (IL-1β) and bradykinin (BK) synergistically stimulate prostaglandin E2 (PGE2) formation in human gingival fibroblasts cultured for 24 h. Neither BK or IL-1β per se, nor their combinations, caused any acute stimulation of cellular cyclic AMP accumulation. BK, but not IL-1β, caused a rapid, transient rise of intracellular Ca2+ concentration ([Ca2+]i), as assessed by recordings of fura-2 fluorescence in monolayers of prelabelled gingival fibroblasts. IL-1β did not change the effect of BK on [Ca2+]i. Ionomycin and A 23187, two calcium ionophores, synergistically potentiated the stimulatory effect of IL-1β on PGE2 formation. Three different phorbol esters known to activate protein kinase C also synergistically potentiated the action of IL-1β on PGE2 formation. Exogenously added arachidonic acid significantly enhanced the basal formation of PGE2. In IL-1β treated cells, the enhancement of PGE2 formation seen after addition of arachidonic acid, was synergistically upregulated by IL-1β. These data show that i) the synergistic interaction between IL-1β and BK on PGE2 formation is not due to an effect linked to an upregulation of cyclic AMP or [Ca2+]i; ii) the signal transducing mechanism by which BK interacts with IL-1β, however, may be linked to a BK induced stimulation of [Ca2+]i and/or protein kinase C; iii) the mechanism involved in the action of IL-1β may, at least partly, be due to enhancement of the biosynthesis of prostanoids mediated by an upregulation of cyclooxygenase activity.

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Phosphorylation of p90 and p52 in response to phorbol-esters in Swiss/3T3 cells overexpressing protein kinase C-alpha.

Molecular Biology of the Cell ◽

10.1091/mbc.3.9.1049 ◽

1992 ◽

Vol 3 (9) ◽

pp. 1049-1056 ◽

Cited By ~ 3

Author(s):

H Eldar ◽

E Livneh

Keyword(s):

Protein Kinase C ◽

Growth Factor ◽

Protein Kinase ◽

Cell Lines ◽

Phorbol Ester ◽

Phorbol Esters ◽

Tumor Promotion ◽

3T3 Cells ◽

Kinase C ◽

Pkc Alpha

Cell lines stably overexpressing protein kinase C (PKC)-alpha were previously described by us. These cell lines were generated by the introduction of the full length cDNA coding for PKC-alpha into Swiss/3T3 cells. Here we show that activation of PKC-alpha by phorbol-esters induced in these cells specific phosphorylation of two cellular proteins p90 and p52. Phosphorylation of p80 (MARCKS protein), previously identified as a substrate for PKC, was also enhanced. Phosphorylated p90 and p52 proteins were associated with particulate membrane-enriched fractions and were extractable with the use of nonionic detergents. Time course analysis of phorbol-ester induced phosphorylation of p90 and p52 revealed maximal stimulation of phosphorylation after 15-30 min. Phosphamino acid analysis showed that phosphorylation of p90 and p52 occurred mainly on serine residues. Phosphorylation of p52 was also on threonine residues. Whereas, phorbol ester activation induced phosphorylation of both p90 and p52, the mitogens platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) enhanced phosphorylation of p90, but not p52. Thus, our studies showed the involvement of PKC-alpha in the regulation of p90 and p52 phosphorylation and provided direct evidence for the role of PKC-alpha in cellular signaling by PDGF and FGF. Moreover, the fact that phosphorylation of p52 was specific to phorbol ester activation may suggest its involvement in tumor promotion. Characterization of p90 and p52 will enable us to reveal the phosphorylation cascade activated downstream to PKC-alpha and to determine their role in mitogenic signaling and tumor promotion.

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Relation of the induction of epidermal ornithine decarboxylase and hyperplasia to the different skin tumor-promotion susceptibilities of protein kinase C?, -? and -? transgenic mice

International Journal of Cancer ◽

10.1002/ijc.1395 ◽

2001 ◽

Vol 93 (5) ◽

pp. 635-643 ◽

Cited By ~ 48

Author(s):

Aaron P. Jansen ◽

Nancy E. Dreckschmidt ◽

Eric G. Verwiebe ◽

Deric L. Wheeler ◽

Terry D. Oberley ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Transgenic Mice ◽

Ornithine Decarboxylase ◽

Tumor Promotion ◽

Skin Tumor ◽

Kinase C

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Protein kinase C and skin tumor promotion

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/0027-5107(95)00142-5 ◽

1995 ◽

Vol 333 (1-2) ◽

pp. 161-172 ◽

Cited By ~ 15

Author(s):

F MARKS

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Tumor Promotion ◽

Skin Tumor ◽

Kinase C

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Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis

AJP Cell Physiology ◽

10.1152/ajpcell.00254.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. C24-C32 ◽

Cited By ~ 36

Author(s):

Elizabeth V. Wattenberg

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Cell Fate ◽

Molecular Mechanisms ◽

Mouse Skin ◽

Tumor Promotion ◽

Skin Tumor ◽

Tumor Promoter ◽

Kinase C ◽

And Function

Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12- O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na+,K+-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.

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