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.