title: Novel thiosemicarbazones regulate the signal transducer and activator of transcription 3 (STAT3) pathway: inhibition of constitutive and interleukin 6-induced activation by iron depletion.
abstract: Pharmacologic manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal how the iron-binding ligands desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibit constitutive and interleukin 6-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which promotes proliferation, survival, and metastasis of cancer cells. We demonstrate that DFO, Dp44mT, and DpC significantly decrease constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines PANC-1 and MIAPaCa-2 as well as the prostate cancer cell line DU145. These compounds also significantly decrease the dimerized STAT3 levels, the binding of nuclear STAT3 to its target DNA, and the expression of downstream targets of STAT3, including cyclin D1, c-myc, and Bcl-2. Examination of upstream mediators of STAT3 in response to these ligands has revealed that Dp44mT and DpC could significantly decrease activation of the nonreceptor tyrosine kinase Src and activation of cAbl in DU145 and MIAPaCa-2 cells. In contrast to the effects of Dp44mT, DpC, or DFO on inhibiting STAT3 activation, the negative control compound di-2-pyridylketone 2-methyl-3-thiosemicarbazone, or the DFO:Fe complex, which cannot bind cellular iron, had no effect. This demonstrates the role of iron-binding in the activity observed. Immunohistochemical staining of PANC-1 tumor xenografts showed a marked decrease in STAT3 in the tumors of mice treated with Dp44mT or DpC compared with the vehicle. Collectively, these studies demonstrate suppression of STAT3 activity by iron depletion in vitro and in vivo, and reveal insights into regulation of the critical oncogenic STAT3 pathway.
authors.affiliation: Department of Pathology and Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Goldie Y L
authors.initials: GY
authors.lastname: Lui
authors.affiliation: Department of Pathology and Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Department of Pathology and Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Sharleen
authors.initials: S
authors.lastname: V Menezes
authors.affiliation: Department of Pathology and Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Department of Pathology and Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Merlot
authors.affiliation: Department of Pathology and Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sahni
authors.affiliation: Department of Pathology and Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia d.richardson@sydney.edu.au.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D007501:Iron; D050796:STAT3 Transcription Factor; D013882:Thiosemicarbazones; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human