Cancer cells communicating junctions

Different types of apparently beneficial activities have been demonstrated in vitro for carotenoid oxidation products, including induction of gap-junctional communications, " growth inhibition of leukemia and cancer cells, induction of apoptosis... 

Connexin 43 is one of the cell membrane gap junction proteins that allow for cell to cell communication. Cancer cell transformation is correlated with the loss of Connexin 43 expression (Hussain et al. 1989, Zhang et al. 1992). Lycopene increased Connexin 43 expression in fetal skin fibroblasts (Stahl et al. 2000), oral cancer KB-1 cells grown in organotypic rafts (Livny et al. 2003) and breast cancer cell lines (Chalabi et al. 2007). 

Antioxidant micronutrient of tomatoes associated with decreased risk for cancer and cardiovascular disease. Enhances gap junction communication between cells and reduces proliferation of cancer cells in culture. 

Furthermore, lycopene enhanced gap junctional communication between the cancer cells and strongly, and dose-dependently, inhibited proliferation of KB-1 human oral tumor cells, thereby pointing to a role in oral cancer. 

In 2012, a group of Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA examined their growth inhibitory effect of 9-cis retinoic acid (30) and a -trans retinoic acid (29) on the formation and degradation of gap junctions, and on junctional communication in three LNCaP eells of an human androgen-responsive prostate cancer cell line. 

Another characteristic of lycopene and other carotenoids that may be relevant to inhibition of cancer cell growth is the modulation of gap junction cell-cell communication processes. In particular, carotenoids including lycopene have been shown to enhance the efficacy of the protein, coimexin43, which helps to ensure the maintenance of the differentiated state of cells and to reduce the probability of unregulated cell division, and which is deficient in many tumors. They may also interact with and enhance the synthesis of... 

Azamia, R., and Loewenstein, W. R., 1971, Intercellular communication and tissue growth. V. A cancer cell strain that fails to make permeable membrane junctions with normal cells, /. Membrane Biol. 6 368. 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

In atherosclerosis and other heart diseases, the role of carotenoids as antioxidants is probable, but for these types of diseases and also for other degenerative diseases such as cancers, non-antioxidant activities constitute other possible prevention mechanisms. These activities are, for example, stimulation of gap junction communications between cells, and the induction of detoxifying enzymes. The... 

Zhang, L. X., R. V. Cooney, and J. S. Bertram. 1991. Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells Relationship to their cancer chemopreventive action. Carcinogenesis 12(11) 2109—2114. 

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

Fitzgerald DJ, Knowles SE, Ballard FJ, Murray AW Rapid and reversible inhibition of junctional communication by tumor promotors in a mouse cell line. Cancer Res 1983 43 3614-3618. 

Noguchi M, Nomata K, Watanabe J, Kanetake H, Saito Y. Changes in gap junction intercellular communication in renal tubular epithelial cell in vitro treated with renal carcinogens. Cancer Letts 1998 122 77-84. 

As discussed in Chapter 16, the question of whether or not athermal levels of microwave fields are toxic is a controversial one. One study, however, found that such microwaves act synergistically with chemical cancer promoters and lead to autonomous cell growth. 711 This effect has been demonstrated in vitro using the combination of cancer promoting phorbol esters co-applied with nonionizing electromagnetic fields. The author of the study hypothesizes that the mechanism of the combined radiation/ chemical effect involves the disruption of normal intercellular communication through gap junctions. 

Upham BL, Rummel AM, Carbone JM, Trosko JE, Ouyang Y, Crawford RB, Kaminski NE (2003) Cannabinoids inhibit gap junctional intercellular communication and activate ERK in a rat liver epithelial cell line. Int J Cancer 104 12-18... 

Klann RC, Fitzgerald D J, Piccoh C, Slaga TJ, Yamasaki H. Gap-junctional intercellular communication in epidermal cell hues from selected stages of SENCAR mouse skin carcinogenesis. Cancer Res i989 49 699-705. 

Banoub, R.W., Femstrom, M., and Ruch, R.J., Lack of growth inhibition or enhancement of gap junctional intercellular communication and connexin43 expression by beta-carotene in murine lung epithehal cells in vitro. Cancer Lett, 108, 35, 1996. 

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