© 1991 Oxford University Press
research-article |
Stimulatory effect of thapsigargin, a non-TPA-type tumor promoter, on arachidonic acid metabolism in the murine keratinocyte line HEL30 and on epidermal cell proliferation in vivo as compared to the effects of phorbol ester TPA
German Cancer Research Center, Institute of Biochemistry, Im Neuenheimer Feld 280, D-6900 Heidelberg, FRG and Department of Biochemistry BC, Royal Danish School of Pharmacy, Universitätsparken 2 DK-2100 Kopenhagen, Denmark
The effect of thapsigargin (Tg), a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type skin tumor promoter, on arachidonic acid and prostaglandin E2 (PGE2) formation in HEL30 keratinocytes and on epidermal DNA synthesis in vitro and in vivo (mouse skin) was investigated and compared with that of the phorbol ester TPA. On a molar basis Tg was 30-fold more potent in inducing the arachidonic acid/PGE2 release than TPA. Applied together, the two agents showed a strong synergistic action. The response critically depended on the presence of Ca2+ in the extracellular medium. While the TPA-induced release was mediated by protein kinase C (PKC) the Tg-induced release was not. In contrast to TPA (1 µM), which is a stimulator of HEL30 DNA synthesis, Tg (0.1–1 µM) inhibited DNA labeling in vitro due to a pronounced cytotoxic effect. TPA did not exhibit such an effect. In vivo both agents were practically equipotent in inducing epidermal DNA synthesis and hyperplasia with TPA having an 
10-fold higher irritating potential than Tg. It is concluded that the hyperplasiogenic and tumor-promoting effect of Tg in vivo is due to cytotoxicity causing cell death and regenerative hyperproliferatlon. Thus, Tg-induced skin tumor promotion seems to resemble tumor promotion by mechanical skin wounding, whereas TPA evokes a more specific, i.e. PKC-mediated response. Since despite these mechanistic differences both agents induce an immediate release of arachidonic acid/PGE2 in keratinocytes, this response may be considered to provide an in vitro parameter for irritancy and tumor promotion.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. E. Rys-Sikora, R. L. Konger, J. W. Schoggins, R. Malaviya, and A. P. Pentland Coordinate expression of secretory phospholipase A2 and cyclooxygenase-2 in activated human keratinocytes Am J Physiol Cell Physiol, April 1, 2000; 278(4): C822 - C833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Serpi, J. Piispala, M. Jarvilehto, and K. Vahakangas Thapsigargin has similar effect on p53 protein response to benzo[a]pyrene–DNA adducts as TPA in mouse skin Carcinogenesis, September 1, 1999; 20(9): 1755 - 1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Li-Stiles, H.-H. Lo, and S. M. Fischer Identification and characterization of several forms of phospholipase A2 in mouse epidermal keratinocytes J. Lipid Res., March 1, 1998; 39(3): 569 - 582. [Abstract] [Full Text]
|
|
|
|
 |
|
 B. J. Ledwith, C. J. Pauley, L. K. Wagner, C. L. Rokos, D. W. Alberts, and S. Manam Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells J. Biol. Chem., February 7, 1997; 272(6): 3707 - 3714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Gundimeda, Z.-H. Chen, and R. Gopalakrishna Tamoxifen Modulates Protein Kinase C via Oxidative Stress in Estrogen Receptor-negative Breast Cancer Cells J. Biol. Chem., June 7, 1996; 271(23): 13504 - 13514. [Abstract] [Full Text] [PDF]
|
|