Molecular mechanisms, tumor-promoting

Although the molecular mechanisms of tumor-promoting action of... 

Tumor promoters alter pathways that cooperate with the genetic changes present in the initiated cell to produce the selective growth of that cell. Generic mechanisms of tumor promotion are shown in Table 24.6. Although the precise molecular/bio-chemical mechanisms of tumor promotion are unknown, we do know that certain receptors, growth factors, transcription factors, cytokines, and kinases are involved in tumor promotion induced by a particular tumor promoter. 

A variefy of chemical agents are known to act as tumor promoters in various systems. However, much of our knowledge of the cellular and molecular mechanisms of tumor promotion has come from studies using the phorbol ester tumor promoters in the mouse skin model and in various cell culture systems. 

Molecular mechanisms by which PMFs exert their anti-inflammatory and anti-tumor-promoting, as well as anti-tumor-invading activities remain poorly understood. However, Ito and co-workers [80] recently presented an excellent study indicating that nobiletin suppressed the TPA-induced binding activity of activator protein-1 and that it may interfere in the phosphatidylinositol 3-kinase pathway, which divergently regulates the production of MMP and its inhibitor. 

As mentioned above many tumor promoters induce a cellular prooxidant state. Because poly(ADP) ribosylation of chromosomal proteins could play a role in active oxygen-induced modulation of gene expression by PMA we studied the effect of antioxidants. As shown in Fig. 2 for human fibroblasts 3229 the extracellular addition of moderate concentrations of CuZn-superoxide dismutase and catalase suppressed the PMA-induced accumulation of poly(ADPR) by 80-100%. Heated catalase was inactive. The low molecular weight antioxidant butylated-hydroxytoluene also suppressed the increase in poly(ADPR). These results suggest that active oxygen produced in a superoxide driven Fenton reaction represents an intermediate in the mechanism of action of PMA. The fact that the same antioxidants had no effect on poly(ADPR) synthesis induced by MNNG further emphasizes the fundamental difference between the two agents. 

Activator protein-1 (AP-1) is an important transcription factor that figures in the inflammation response. AP-1 is a dimeric complex of the protooncoproteins jun and fos that is induced by growth factors, cytokines, tumor promoters, and sunlight [39]. Activation of AP-1 increases the transcription of cytokines, such as interleukin-2, and certain matrix metalloproteinases [40]. In the presence of t-RA, RARs can inhibit the actions of AP-1. Reciprocally, elevated expression of either the jun or fos components of AP-1 can prevent activation of RAREs by RARs. This repression of gene transcription, called transrepression, is a well-known mechanism for crosstalk between retinoid receptors and AP-1 [41-43]. The molecular mechanism of transrepression described for in vitro systems is dependent on the presence of t-RA and is believed to involve direct or indirect protein-protein interactions between retinoid receptors and AP-1 components (jun and fos), and/or competition between retinoid receptors and AP-1 for a common factor (or factors) required for their activities [42, 43]. However, this phenomenon studied in the context of photoaging of human skin in vivo has revealed a novel mechanism. 

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