External zinc stimulates proliferation of tumor Hep-2 cells by active modulation of key signaling pathways.
The effect of external zinc supplementation (10 and 35 micromol) on cell proliferation and mitogenic signaling of Hep-2 tumor cells was examined during 72 h of treatment. Zinc levels were manipulated by using zinc-free cultivation medium with or without addition of zinc ions. Proliferation of Hep-2 cells exposed to zinc-free medium decreased in a time-dependent manner and corresponded to decreasing intracellular zinc content. Hep-2 cells accumulated in G(0)/G(1) phase, showed reduced abundance of AKT and NF-kappaB as well as of anti-apoptotic Bcl-2 and Bcl-XL proteins. Zinc supplied to Hep-2 cells maintained in the presence of zinc-free medium stimulated their proliferation as well as mitogenic signaling which paralleled increasing intracellular zinc content. In zinc-exposed Hep-2 cells, several changes in various mitogenic signaling pathways were noted such as enhanced expression of p53, AKT and MAP kinases, NF-kappaB and increased DNA binding of AP-1 family. Also, supplementation with zinc of Hep-2 cells resulted in the suppression of key apoptotic molecules such as Bax protein and increased expression of anti-apoptotic Bcl-2 and Bcl-XL proteins. Since only the highest supplied zinc concentration (35 micromol) induced oxidative stress, it is reasoned that the observed activation of pro-survival signaling occurs both directly and indirectly. These data show that zinc may stimulate growth and proliferation of some tumor cells by a combination of internal mechanisms with a varying contribution of external signaling pathways too.
Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Králové, Charles University in Prague, Simkova 870, 500 38 Hradec Králové, Czech Republic. rudolf@lfhk.cuni.cz
Emil
E
Rudolf
Miroslav
M
Cervinka
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D008668:Metallothionein / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D008668:Metallothionein; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D015032:Zinc