The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel

<p>Abstract</p> <p>Background</p> <p>Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out.</p> <p>Methods</p> <p>Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI₅₀ data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested <it>in vitro</it> for the ability to influence tumor susceptibility to arsenic trioxide.</p> <p>Results</p> <p>A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down.</p> <p>Conclusions</p> <p>In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.</p

Taxation and Foreign Direct Investment Inflows: Time Series Evidence from the US

This study investigates long run and short run relationships between the corporate income tax rate and foreign direct investment (FDI) inflows to the US. The tax rate is found to exert a significant negative effect on total FDI and transfer fund inflows in the long run. A 1% decrease in the tax rate would increase total FDI by 2.4% and transfer funds by 4.2%. Collectively, results suggest that the US can use tax policies to attract FDI from abroad. Concern over the possibility of tax competition among countries to attract foreign capital is warranted

Corruption and Foreign Direct Investments: A Panel Analysis

This paper investigates the effects of corruption on foreign direct investment (FDI) inflows controlling for other relevant determinants using a panel data approach for 45 countries over 1997-2004. While economic theory suggests that corruption should discourage FDI, many notably corrupt countries receive substantial FDI - an anomaly worthy of investigation. In common with other empirical work, we find no statistically significant impact of corruption on FDI. This suggests that policies designed to attract additional foreign FDI should focus on corporate income taxes and other determinants of investment rather than on the intractable problem of reducing the level of corruption

The impact of corporate income tax rate on foreign direct investment in Australia and implications for technology transfer

FDI is an important channel through which technology can be transferred across countries. The increased mobility of capital and the globalisation have influenced tax competition among countries to attract foreign investment. This paper investigates the effects of company tax rate on FDI stocks into Australia over the period 1960-2003 using time series econometric techniques. The results show that Australia has a potential to attract FDI by lowering its company tax rate. The findings suggest that lowering the taxes by host country to attract FDI would also in effect help the country to accumulate its technological stock enhancing its global competitiveness

Do recent data provide evidence that the US trade deficit will correct itself?

We use monthly data from the 23 largest US trading partners for the years 1985–2005 to examine the long-run relationship between imports and exports. Results indicate that a long-run equilibrium relationship is identifiable in most of the countries we analyse. However, the country with which the US has the largest trade deficits do not exhibit any long-run relationship, indicating that any self-correcting mechanism on the trade account is either nonexistent or slow in these cases. Further, the presence of a long-run relationship is most apparent in the countries with which the US has a trade surplus. Taken together, these results provide evidence that continued growth in the US trade deficit is likely.

Transcription of gonadotropin β subunit genes involves cross-talk between the transcription factors and co-regulators that mediate actions of the regulatory hormones

10.1016/j.mce.2006.03.024Molecular and Cellular Endocrinology2521-2167-183MCEN