You are here:
EFFECT OF ARSENICALS ON ULTRAVIOLET-RADIATION-INDUCED GROWTH ARREST AND RELATED SIGNALING EVENTS IN HUMAN KERATINOCYTES
Citation:
Mudipalli, A, R D. Owen, AND R J. Preston. EFFECT OF ARSENICALS ON ULTRAVIOLET-RADIATION-INDUCED GROWTH ARREST AND RELATED SIGNALING EVENTS IN HUMAN KERATINOCYTES. International Journal of Oncology. D.A. Spandidos, , Greece, 27(3):769-778, (2005).
Impact/Purpose:
To determine whether arsenicals are capable of overriding the growth arrest caused by UV treatment, leading to selective proliferation
Description:
The molecular mechanisms mediating arsenic-induced carcinogenesis are not well understood. The role of confounding factors such as ultraviolet radiation (UV), add another level of complexity to the study of arsenic carcinogenesis and the cancer risk assessment to humans. We hypothesized that arsenicals are capable of overriding the growth arrest caused by UV treatment and may lead to selective proliferation. To test this hypothesis, a primary normal human epidermal keratinocyte (NHEK) cell culture model was used. One group was pre-exposed to UVB (100 mJ/cm2) that arrested a majority (~95%) of cells in GO/G1 (+UV) and a second group was not exposed to UV (-UV). Treatment of cells with various arsenicals [0-12 ?M of inorganic arsenite (iAs), 0-2 ?M of methyl oxoarsine (MM As III) and 0-3 ?M of iododimethyl arsine (DMAs III)] indicated a concentration dependent increase in proliferation at 24 h in the order DMAs III> MMAs III > iAs. Flow cytometric analyses revealed differential effects on cell cycle
distribution. Analysis of a battery of cell cycle proteins (cyclin D1, cdk5, PCNA and cdc25A and cdc25C) indicated exposure-specific differential expression profiles. Increased activation of JNK phosphorylation (5-10 fold) in the +UV group and the synergistic increase with methyl arsenicals suggested that JNK might be involved in cell survival and proliferative signaling. Induction of EGF levels and increased phosphorylation of EGF receptor by arsenicals (?UV) suggested that the EGF signaling pathway might mediate arsenical-induced cell proliferation of NHEK cells. Differential activation of ERK1/2 by arsenicals (? UV) suggested that EGF-mediated cell proliferation by arsenicals in UV treated NHEK cells may not involve ERK activation. Taken together, the data suggest that both UV exposure and methylation status of the arsenicals dictate the participation of key cell cycle proteins and related signaling events in arsenical-induced cell proliferation.