palytoxin and Skin-Neoplasms

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.

Topics: Acrylamides; Animals; Carcinogens; Cnidarian Venoms; Humans; Signal Transduction; Skin Neoplasms

Previous studies have shown that structurally diverse tumor promoters can modulate protein kinases involved in signal transduction. In this study, we show that palytoxin, a potent non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor promoter, induces a signaling pathway leading to the activation of the stress-activated protein kinases/c-Jun N-terminal kinases (JNK) in Swiss 3T3 fibroblasts. Treatment of cells with doses as low as 0.1 mN palytoxin results in significant activation of JNK. In contrast to epidermal growth factor, which induces a transient activation of JNK in Swiss 3T3 cells, palytoxin causes prolonged enzyme activation. Since stimulation of ion flux appears to play an important role in the mechanism of action of palytoxin in other systems, we investigated the role of sodium and calcium in the activation of JNK: (a) our results show that incubation of Swiss 3T3 cells in a sodium-free medium dramatically reduced the magnitude of JNK activation by palytoxin; and (b) we found that the sodium ionophore gramicidin activates JNK. Together, these results suggest that sodium influx, which is a hallmark of palytoxin action, may play a key role in the activation of JNK by palytoxin. Our results indicate that calcium influx is not necessary or sufficient for palytoxin-induced activation of JNK. In contrast to palytoxin, the TPA-type tumor promoter phorbol 12,13-dibutyrate and the non-TPA-type tumor promoters thapsigargin and okadaic acid do not appear to activate JNK in this system. In contrast to phorbol 12,13-dibutyrate, palytoxin does not activate the p42/p44 mitogen-activated protein kinases. Our results demonstrate that Swiss 3T3 fibroblasts, palytoxin can activate a protein kinase signaling pathway that is distinct from that activated by the prototypical phorbol ester tumor promoters and other potent skin tumor promoters.

Topics: 3T3 Cells; Acrylamides; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Carcinogens; Cnidarian Venoms; Enzyme Activation; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 9; Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Signal Transduction; Skin Neoplasms; Sodium; Tetradecanoylphorbol Acetate

Ten new tumor promoters which are structurally different from TPA but of similar biological activity were found. Based on their binding to the phorbol ester receptors of cell membranes, these new tumor promoters were classified as TPA-type tumor promoters, teleocidin and aplysiatoxin, which like TPA, activated protein kinase C in vitro, whereas two non-TPA-type tumor promoters, palytoxin and thapsigargin did not induce ODC activity in mouse skin, adhesion of HL-60 cells or activation of protein kinase C, but did show tumor-promoting activity in a two-stage carcinogenesis experiment. Although these two types of tumor promoter exert their tumor-promoting activities through different pathways, production of prostaglandin E2 by rat macrophages was induced by both the TPA-type and non-TPA-type promoters. Therefore, stimulation of arachidonic acid metabolism is suggested to be one of the important biological activities for tumor promotion.

Topics: Acrylamides; Animals; Arachidonic Acid; Arachidonic Acids; Carcinogens; Cnidarian Venoms; Enzyme Activation; Humans; Lyngbya Toxins; Mice; Neoplasms, Experimental; Phorbols; Plant Extracts; Protein Kinase C; Receptors, Cell Surface; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Thapsigargin

Palytoxon, which is a toxin with a molecular weight of 2681 daltons isolated from a marine coelenterate, is a potent skin irritant. However, it did not induce ornithine decarboxylase in mouse skin, or adhesion of human promyelocytic leukemia cells (HL-60). Moreover, it did not inhibit the specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to a mouse skin particulate fraction or activate protein kinase C isolated from mouse brain in vitro. Since palytoxin showed strong irritation on mouse ear in one short-term screening test for a promoter, it was examined in a two-stage carcinogenesis experiment. The incidence of tumors in a group of mice treated with 7,12-dimethylbenz[a]anthracene plus palytoxin was 62.5% in week 25. These tumors were identified histologically as seven papillomas and one carcinoma. This paper reports the potent tumor-promoting activity of palytoxin, which is classified as a non-TPA-type tumor promoter.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acrylamides; Animals; Carcinogens; Cnidarian Venoms; Enzyme Induction; Female; Lyngbya Toxins; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Skin Neoplasms; Tetradecanoylphorbol Acetate

The activity of histidine decarboxylase (HDC) increased by a factor of 10 after a single application of 12-O-tetradecanoylphorbol-13-acetate (TPA). The HDC-inducing activity of other phorbol esters paralleled their tumor-promoting activity. Application of some indole alkaloids, which have been shown to be a new class tumor promoter, also induced the increase in HDC activity. The cell type responsible for this increase was examined. First, pieces of the skin were separated into epidermis and dermis after application of TPA. In contrast with ornithine decarboxylase, the HDC activity increased in the dermis. Second, genetically mast cell-deficient W/Wv and Sl/Sld mice were used. Although most histamine in the dermis is in the mast cells, the increase in HDC activity in W/Wv mice was comparable to that in congenic +/+ mice. However, no significant increase in HDC activity was detected in the skin of the Sl/Sld mice. Histological examination revealed that the magnitude of inflammatory cell infiltration was much less in the skin of Sl/Sld mice than in the skin of +/+ or W/Wv mice. The increase in HDC activity and the inflammatory cell response in the skin of W/Wv mice were abolished by prior X-ray irradiation, and were restored by subsequent bone marrow transplantation. Thus, inflammatory cells may be responsible for at least a part of the increase in HDC activity after application of tumor promoters.

Topics: Acrylamides; Animals; Carboxy-Lyases; Carcinogens; Cnidarian Venoms; Histamine; Histidine Decarboxylase; Leukocytes; Lyngbya Toxins; Mast Cells; Mice; Mice, Mutant Strains; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate