PT  - JOURNAL ARTICLE
AU  - Goldie Y.L Lui
AU  - Zaklina Kovacevic
AU  - Sharleen Menezes
AU  - Danuta S Kalinowski
AU  - Angelica M Merlot
AU  - Sumit Sahni
AU  - Des R Richardson
TI  - Novel Thiosemicarbazones Regulate the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway: Inhibition of Constitutive and Interleukin 6 (IL6)-Induced Activation by Iron Depletion
AID  - 10.1124/mol.114.096529
DP  - 2015 Jan 05
TA  - Molecular Pharmacology
PG  - mol.114.096529
4099  - http://molpharm.aspetjournals.org/content/early/2015/01/05/mol.114.096529.short
4100  - http://molpharm.aspetjournals.org/content/early/2015/01/05/mol.114.096529.full
AB  - Pharmacological manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal 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 (IL6)-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 dimerized STAT3 levels, binding of nuclear STAT3 to its target DNA, and 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 revealed Dp44mT and DpC could significantly decrease activation of the non-receptor 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 (Dp2mT), 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 to 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.