The tumor promoter pristane activates transcription by a cAMP dependent mechanism

Abstract

Pristane is a naturally occurring isoprenoid which is believed to be derived from the phytyl moiety of chlorophyll. Thus it is not surprising that pristane is present in many common fruits or vegetables and furthermore can be detected in tissues of fish and mammals. Using the rat as an animal model, pristane can function as a potent tumor promoter. It is conceivable that pristane could play a role in the development of certain malignancies in higher mammals since it is commonly found in the diet. At the molecular level, pristane can induce changes in the plasma membrane, alter the conformation of chromatin, as well as selectively activate gene expression. This study was undertaken to identify specific transcriptional motifs which are responsive to pristane. A transcriptional promoter which contained a cAMP response element (CRE) was consistently stimulated by pristane in several mouse and primate cell lines. A promoter construct which contained a single copy of the TPA response element (TRE) was also activated by pristane but surprisingly a promoter which contained multiple copies of the TRE was not. Activation of the TRE required 10 fold higher concentrations of pristane relative to activation of the CRE. Within two hours after addition of pristane to monkey fibroblasts (CV-1) levels of cAMP were increased more than two fold relative to controls. These data indicated that pristane can increase the level of cAMP in CV-1 cells and consequently stimulate transcriptional promoters which contain a CRE.

Analysis of transcriptional activation of a cyclic AMP response element by 2,6,10,14‐tetramethylpentadecane (pristane) in JB6 mouse epidermal cells

“…Several studies have demonstrated that pristane activates transcription and that a CRE appears to be a primary target for transcriptional activation by pristane [21,22,30]. These studies demonstrate point mutations in the CRE eliminated activation ( Figure I), suggesting that proteins binding a functional CRE were activated when cells were treated with pristane.…”

“…In large part, adenyl cyclase, phosphodiesterase, and PKA regulate CRE-dependent transcription [23,24,4143]. Because pristane activates CRE-dependent transcription [22,30] (Figure I), the levels of these enzymes were measured after P+ or P-cells were treated with pristane. In P+ and P-cells, the levels of adenyl cyclase activity were similar to those in control cells (data not shown).…”

“…Our study was undertaken to examine the effects pristane has on P+ and P-cells with respect to CRE activation. Because pristane activates a CRE in several mammalian cell lines [21,22] and induces neoplastic transformation of P+ but not P-cells [30], it was hypothesized that pristane activates novel genes containing a CRE in P+ cells that are required for neoplastic transformation. To test this hypothesis, we conducted experiments that examined transcriptional activation of a CRE and the interaction of nuclear proteins with a CRE in P+ and Pcells.…”

Use of Nigella sativa Linn. Supercritical Carbon Dioxide Extract for Targeting the Angiogenesis Cascade

“…In addition, the extracts C3 and D3 exhibited presence of pristane. Previous studies reported various bioactivities of these compounds, such as cytotoxic and antitumour potential of TQ [21,41], thymohydroquinone [55,56] and pristine [57].…”

Effects of Pristane on Cytochrome P450 Isozyme Expression in Rat Tissues

“…In addition, pristane exhibited tumor enhancing properties in our Copenhagen rat model in which direct Peyer’s patches (PP) injection with a low dose of 3-methylcholanthrene (3-MC) led to only B lymphoid malignancies, a high 3-MC dose treatment induced thymic lymphomas but no B cell malignancies, and co-treatment with 3-MC and pristane lead to higher frequency and decreased latency of 3-MC induced lymphoid malignancies [ 9 ]. Also, pristane elicited marked effects on transactivation of transfected genes [ 10 – 13 ]. These activities are comparable to 12-O-tetradecanoylphorbol 13-acetate (TPA), a known tumor promoter [ 14 ].…”