Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: enhanced survival and mutagenesis.
Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na(2)CrO(4)), the soluble oxyanionic dissolution product of certain particulate chromates, which are well-documented human respiratory carcinogens. In vitro soluble Cr(VI) induces a wide spectrum of DNA damage, in both the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate (SOV). Notably, SOV abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after SOV treatment was predominantly due to a bypass of cell cycle arrest, as there was no effect of the PTP inhibitor on Cr-induced apoptosis. Moreover, the SOV effect was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by SOV was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in Cr(VI)-induced expression of cell cycle promoting genes. Importantly, SOV resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of certain types of DNA damage may lead to increased genomic instability, via bypass of cell cycle checkpoints.
Bae
Dongsoon
D
Department of Pharmacology and Physiology, The George Washington University Medical Center, Washington, DC, USA.
Camilli
Tura C
TC
Chun
Gina
G
Lal
Madhu
M
Wright
Kristen
K
O'Brien
Travis J
TJ
Patierno
Steven R
SR
Ceryak
Susan
S
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002857:Chromium / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D016296:Mutagenesis / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D002857:Chromium; C074702:chromium hexavalent ion; D017027:Protein Tyrosine Phosphatases