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

Abstract

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.

Fig. 1

Palytoxin modulates MAP kinase activity by different mechanisms. (A) Palytoxin may activate ERK through an autocrine mechanism that involves the production of prostaglandins. (B) Palytoxin can activate stress activated protein kinases through the stimulation of upstream protein kinase cascades. Palytoxin activates JNK through a mechanism that requires activation of the MAPK kinase SEK1. Depending on the cell type, palytoxin activates p38 through protein kinase cascades that require the MAPK kinases MKK3 and MKK6. Although not depicted in this scheme, in COS cells, palytoxin can also activate p38 through a protein kinase cascade that requires SEK1. (C) In cells that express oncogenic Ras, palytoxin can increase ERK activity by disrupting the action of MKP-3, a dual specificity protein phosphatase that specifically dephosphorylates and inactivates ERK.