In fact, adiponectin has been considered to possess anti-oxidant properties

In fact, adiponectin has been considered to possess anti-oxidant properties

uclear receptors, and the observed pro-oncogenic or tumor suppressor-like activity is dependent on the subcellular location PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19713189 of the receptor. Several different structural classes of ligands bind NR4A1 and these include cytosporone B and related analogs, C-DIMs, ethyl 2-acetate , and 1-nonan-1-one. Cytosporone B and related compounds and 1-nonan-1-one induce nuclear export of NR4A1 and TMPA antagonizes nuclear NR4A1-LKB1 interactions but does not affect NR4A1-dependent transactivation. In contrast, our previous studies in pancreatic, lung and colon cancer cells show that C-DIM/NR4A1 antagonists act on nuclear NR4A1 and do not induce nuclear export of the receptor and these compounds also decrease NR4A1dependent transactivation. Kidney injury can induce NR4A1 expression in non-tumor tissue, and one study reported the NR4A1 was expressed in 786-O cells and NR4A1 mRNA was more highly expressed in tumors from patients with RCC compared to surrounding non-tumor tissue. Currently, we are accumulating tumors from kidney cancer patients to investigate the tumor-type specific expression and prognostic significance of NR4A1. We further investigated the pro-oncogenic functions of NR4A1 by RNAi and compared the results with that observed after treatment of ACHN or 786-O cells with PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19711015 two prototypical NR4A1 antagonists, DIM-C-pPhOH and DIM-CpPhCO2Me. Both NR4A1 knockdown and the NR4A1 antagonists inhibited ACHN and 786-O cell proliferation and transactivation, and DIM-C-pPhOH also inhibited tumor growth in athymic nude mice bearing ACHN cells as xenografts and siNR4A1 and NR4A1 antagonists also induced apoptosis in these cell lines. These effects are comparable to 12 / 17 Inhibition of Renal Cell Adenocarcinoma by NR4A1 Antagonists Fig 7. siNR4A1 and NR4A1 antagonist inhibit mTOR in 786-O cells. Cells were transfected with siNR4A1 and treated with DIMI-C-pPhOH and DIM-C-pPhCO2Me, and whole cell lysates were analyzed by western blots as outlined in the Materials and Methods. 221244-14-0 Induction of sestrin 2 by western 13 / 17 Inhibition of Renal Cell Adenocarcinoma by NR4A1 Antagonists blots was determined in 786-O cells treated with DIM-C-pPhOH and DIM-C-pPhCO2Me or transfected with siNR4A1 in the presence or absence of 5 mM GSH. doi:10.1371/journal.pone.0128308.g007 previous studies in pancreatic, lung and colon cancer cell lines, suggesting the potential therapeutic potential for C-DIMs in treating RCC in patients that overexpress NR4A1. Fig 1A illustrates three pro-oncogenic pathways and related genes that are regulated by NR4A1 in pancreatic, lung and colon cancer cell lines, and we have also observed these NR4A1-dependent response/pathways in other cancer cell lines. NR4A1 in combination with p300 coactivates survivin and other Sp1-regulated genes, and results in Fig 4 show that survivin, bcl-2 and the EGFR were regulated by NR4A1 in RCC cells. All three of these Sp-regulated genes play a role in cancer cell growth and survival and some studies show that expression of survivin, EGFR and bcl-2 are negative prognostic factors for patients with RCC. Thus, NR4A1 regulation of these genes in RCC contributes to the tumor phenotype, and inhibition of these genes by C-DIM/NR4A1 antagonists in RCC cells and tumors is an important component of their antineoplastic activity. A second NR4A1-regulated pathway in cancer cells is associated with regulation of genes such as TXNDC5 and IDH1 that maintain high levels of redox equivalents and decrease intracellular stress. Knoc

Proton-pump inhibitor

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