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- W2174702422 abstract "AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA286 Increasing numbers of studies reveal that occupational and environmental exposures to certain hexavalent chromium compounds are associated with upper respiratory tract and pulmonary carcinogenesis through poorly defined mechanism(s) of action. Inappropriate activation/inactivation of key signals that control cell survival after genotoxic insult can contribute to autonomous cell growth and carcinogenesis. The PI3K/AKT signaling cascades are important integrators of growth and survival signals in lung carcinogenesis. Our previous studies showed that maintenance of protein tyrosine phosphorylation by PTP inhibition, which is coincident with AKT activation, overrides Cr6+-induced growth arrest and enhances clonogenic survival in human lung fibroblasts (HLFs). To test the hypothesis that AKT activation is a key determinant of cellular survival response after Cr6+ genotoxic insult, we examined the effect of AKT1 knockdown on cell survival after Cr6+exposure and PTP inhibition. HLFs were transiently transfected with akt1 siRNA or d/n akt1 plasmid via nucleofector. Transfected cells were treated with 0-2μM Cr6+ in the presence and absence of PTP inhibition with sodium orthovanadate, for 24h, then washed and replated to examine clonogenic survival. Expression level of akt1 mRNA and AKT1 proteins was determined by quantitative PCR and Western blot, respectively. PTP inhibition decreased Cr6+-induced clonogenic lethality even after AKT1 silencing although AKT1 activity was sufficient to override Cr6+-induced G1/S arrest. This finding prompted us to examine other survival pathway(s) that may contribute in the maintenance of cellular survival after abrogation of AKT signaling. ERK was hyperactivated after AKT1 silencing in the presence of PTP inhibition. Moreover, phosphotyrosine profiling array showed that PTP inhibition following Cr6+ treatment increased phosphorylation status of adaptor phosphotyrosine proteins, FGR and ABL, which are upstream of both AKT and ERK pathways. These findings suggest that the balance between AKT and ERK pathways under control of upstream regulatory phosphotyrosine kinases may be a molecular mechanism to govern cell survival in the face of genotoxic insult with or without PTP inhibition in HLFs. In conclusion, AKT activation may not be solely necessary by itself to enhance clonogenic survival after Cr6+ insult and PTP inhibition, and the balance between AKT and ERK activation after PTP inhibition may be critical for overriding Cr6+-induced growth arrest/death signaling. Studies on the roles of AKT/ERK crosstalk in genotoxin-induced clonogenic death are currently being examined and will add new insights to the understanding of Cr6+-mediated lung carcinogenesis. Supported by NIH grant CA 107972" @default.
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- W2174702422 date "2007-05-01" @default.
- W2174702422 modified "2023-09-27" @default.
- W2174702422 title "Significance of AKT and ERK activation in clonogenic survival after Cr6+ exposure and protein tyrosine phosphatase (PTP) inhibition" @default.
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