2-Methoxyestradiol mediated signaling network in pancreatic cancer.
2-Methoxyestradiol (2-ME), an endogenous metabolite of 17 beta-estradiol, is known to be a potent inhibitor of neovascularization. Our previous studies have shown that 2-ME can suppress growth of pancreatic tumor cells in vitro and in vivo by the induction of apoptosis (Cancer Res 66: 4309-18, 2006). In order to better comprehend the signaling modulators of 2-ME in pancreatic cancer, we employed a PowerBlot Western Array screening system. Our proteomic profiling has provided framework to define the novel mechanisms of actions of 2-ME in pancreatic cancer. Interestingly, this high-throughput analysis identified proteins such as Rac1, Gelsolin, Glucocorticoid receptor (GR), Smad 2/3, Smad 4, IRS-1, which were not previously reported with 2-ME response. Interestingly, 2-ME modulated down regulation of GR level is accompanied by NF-k B activation in 2-ME responsive but not in resistant pancreatic cancer cells. In view of this observation, possible reciprocal relationship between GR and NF-kappaB activation might be an important regulatory factor in 2-ME mediated demise of a subpopulation of pancreatic cancer cells.
Basu
Aruna
A
Center for Biomedical Sciences, Department of Pharmacology, Case Comprehensive Cancer Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109, USA. abasu@metrohealth.org
Haldar
Subrata
S
D000077584:2-Methoxyestradiol; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018797:Cell Cycle Proteins; D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D000077584:2-Methoxyestradiol