The NF B family of transcription

The NF-κB family of transcription factors is involved in acquisition of resistance to anticancer drugs as well as to apoptosis. NF-κB-mediated mdr1 gene upregulation is part of the anti-apoptotic protection mechanism of proximal tubule (PT) hbv against cadmium-induced oxidative stress and apoptosis [63]. Bentires-Alj et al.[69] have recently shown a new relationship between NF-κB and resistance to chemotherapy through the regulation of human mdr1 gene expression since the inhibition of NF-κB activity sensitizes resistant colon cancer cells to daunomycin through a decreased mdr1 gene expression. In addition, NF-κB seems to be an inducer of anti-apoptotic genes [70]. B cell chronic lymphocytic leukemia presents a strong resistance to apoptosis inducing agents due to expression of antiapoptotic genes such as the inhibitor of apoptosis protein (IAP) and TNF receptor associated protein TRAF gene families [71] which are NF-κB target genes. Hodgkin’s disease tumor cells constitutively activate NF-κB p50 in Hodgkin/Reed-Sternberg cells preventing apoptosis under stress conditions [72]. Moreover, it is now admitted that most of the anticancer drug families [73], [74], [75], [76] have in common the activation of NF-κB [77] which leads to chemoresistance. Thus, inhibition of 5-fluorouracil-activated NF-κB by disulfiram enhances cytotoxicity of the DNA synthesis inhibitor in colorectal cancer cell lines [78] and activation of NF-κB by topoisomerase poisons such as SN38 and doxorubicin protects HeLa cells from the apoptotic effect of the drugs [79]. We show here that GSTP1-1 gene expression is regulated by NF-κB as a wide range of genes involved in carcinogenesis and in apoptosis inhibition. NF-κB contributes to the age-associated up-regulation of cycloxygenase-2 [80] and controls the over-expression of the 12-lipoxygenase in human erythroleukemia cells [81]. As well, manganese superoxide dismutase (MnSOD) expression is induced by NF-κB in epithelial cancer cells in response to TNFα [82]. In the same way, GSTP1-1 protein is involved in carcinogenesis and in resistance to apoptosis. Indeed, Gilot et al.[83] demonstrated that GSTP1-1 can inhibit Jun N-terminal kinase (JNK), preventing apoptosis in rat hepatocytes and GSTP1/P2(−/−) knock-out mice present increased JNK activity in liver and lung [84]. Furthermore, GSTP1-1 is up-regulated in chronic lymphoid leukemia [85] and its overexpression has been associated with a severe prognosis in B cell lymphoma [86]. In conclusion, we report for the first time the binding activity of a functional NF-κB site upstream of the minimal promoter of the GSTP1-1 gene in K562 leukemia cell line whereas the previously described NF-κB like sequence (−98 to −89) in the minimal promoter is not able to bind NF-κB in our experimental conditions and cellular model. Together, our results show the activation of the GSTP1-1 gene during inflammation and potentially during cancer. Further identification of the mechanisms underlying transcriptional control of GSTP1-1 gene will be important for the development of novel therapeutic strategies in chemoresistant leukemia.
Acknowledgements
Introduction Breast cancers possess fundamentally altered metabolism that drives their pathogenic features. Since Otto Warburg's seminal discovery in the 1920s that cancer cells have heightened glucose uptake and aerobic glycolysis, recent studies have identified many other biochemical alterations in cancer cells, including heightened glutamine-dependent anaplerosis and de novo lipid biosynthesis, which serve as metabolic platforms for breast cancer cells to generate biomass for cell division and metabolites that modulate cancer cell signaling, epigenetics, and pathogenicity (Benjamin et al., 2012, Cantor and Sabatini, 2012, Pavlova and Thompson, 2016). While targeting dysregulated metabolism is a promising strategy for breast cancer treatment, the metabolic pathways that drive pathogenicity in breast cancer subtypes that are correlated with heightened malignancy and poor prognosis remain poorly understood.