Mechanism of up-regulated gap junctional intercellular communication during chemoprevention and chemotherapy of cancer

Abstract

To develop a strategy for efficacious intervention in order to prevent or treat various cancers, one must understand the basic mechanism(s) by which various anticancer dietary factors prevent or reverse the tumor promotion or progression phases. Carcinogenesis is a multistage, multimechanism process, involving the irreversible alteration of a stem cell (the “initiation” phase), followed by the clonal proliferation of the initiated stem cell (the “promotion” phase), from which the acquisition of the invasive and metastatic phenotypes are generated (the “progression” phase). While intervention to prevent or treat cancer could occur at each step, the objective of this presentation will focus on the rate limiting step, the promotion phase. Gap junctional intercellular communication (GJIC) has been hypothesized to regulate growth control, differentiation and apoptosis. Most normal, contact-inhibited cells have functional GJIC, while most, if not all, tumor cells have dysfunctional homologous or heterologous GJIC. Cancer cells are characterized by the lack of growth control, by the inability to terminally differentiate and by resistance to apoptosis. Chemical tumor promoters (phorbol esters, DDT, phenobarbital, unsaturated fatty acids, saccharin, etc.) inhibit GJIC in a reversible fashion and at doses above particular chemical thresholds. Various oncogenes (e.g. ras, raf, neu, src, mos) down-regulate GJIC while several tumor suppressor genes can up-regulate GJIC. Antitumor promoters (retinoids, carotenoids, green tea components) and antioncogene drugs (i.e. lovastatin) can up-regulate GJIC. Transfection of gap junction genes (“connexins”) into GJIC-deficient tumor cells can restore GJIC, growth control and reduce tumorigenicity. On the other hand, antisense gap junction genes can convert the phenotype of a non-tumorigenic cell to that of a tumorigenic one. Recently, a specific connexin knockout mouse was shown to have a higher frequency of spontaneous and induced liver cancers. Evidence from these studies clearly suggests that dietary factors can modulate GJIC by inducing various signal transducing systems. The modulation can either down-regulate GJIC and lead to tumor promotion or it can up-regulate GJIC and lead to suppression of the initiated cells. Multiple mechanisms of up- or down-regulation of GJIC exist, as well as multiple types of pre-malignant and malignant tumor cells that are unable able to have functional GJIC. GJIC can be down-regulated by mutations and by epigenetic means. Alteration of gene expression at the transcriptional, translational or post-translational levels would require specific dietary prevention or treatment of cancer. In conclusion, if dietary prevention or treatment of cancer is to occur, it must ameliorate the growth-stimulatory effects, above threshold levels, of chemicals, growth factors or hormones, that trigger various mitogenic/antiapoptotic signal transducing systems that block GJIC.