Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1伪. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxia-inducible genes critical for cancer progression. The observed effects are compound-specific and dose-dependent. Controlling gene expression with designed small molecules targeting the transcription factor-coactivator interface may represent a new approach for arresting tumor growth.
Objectives We investigated the signaling pathways activated in response to Interleukin (IL-6) in pancreatic cell lines, with a focus on signal transducer and activator of transcription 3 (STAT3) and proto-oncogene serine/threonine-protein (Pim-1) kinase. Methods IL-6 receptor (IL-6R) expression and IL-6 induced cell signaling was measured by Western blotting in human pancreatic cell lines. Cucurbitacin I was used as a pharmacological tool to investigate the role of STAT3 in Pim-1 activation. Stably over-expressing Pim-1 kinase cell lines were characterized for their response to IL-6 in vitro, and for their growth rate as flank tumors in scid mice. Results IL-6R was expressed across multiple cancer cell lines. In Panc-1 cells, IL-6 treatment increased expression of P-STAT3 and Pim-1 kinase. Cucurbitacin I treatment alone increased pErk1/2 expression in wild-type and Pim-1 over-expressing cell lines and resulted in exaggerated Pim-1 kinase protein levels in control and IL-6 stimulated cells, suggesting upregulation of Pim-1 may be partially STAT3 independent. Pim-1 over-expression did not significantly impact growth rate in vitro or in vivo in Panc-1 or MiaPaCa2 cell lines. Conclusions IL-6 activates STAT3 and stimulates Pim-1 kinase in pancreatic cell line models. The regulation and consequence of Pim-1 expression appears to be highly context dependent.
Introduction: IL-6 has both diagnostic and prognostic significance in pancreatic cancer. We investigated the signaling pathways activated in response to IL-6 in pancreatic cell lines, with a focus on STAT-3 and Pim-1 kinase. Methods: IL-6 receptor (IL-6R) expression was evaluated by Western blot analysis across a panel of human pancreatic cell lines. Panc-1 and MiaPaCa2 cell lines were serum starved for 24 hrs and then treated with 100 ng/mL of IL-6 for various time courses from 0 to 6 hr. STAT-3 activation and Pim-1 kinase protein levels were assessed in the presence and absence of IL-6 by Western blot analysis. The ability of cucurbitacin B to block both STAT-3 and Pim-1 activation, and inhibit cell proliferation was investigated. Stably transfected Pim-1 kinase over-expressing cell lines were generated and characterized for their response to IL-6 in vitro, and their growth rate in vivo as flank tumors in scid mice. Results: IL-6R is broadly expressed across multiple cancer cell lines, with the highest expression observed in the Panc-1 cell line. IL-6 stimulation resulted in increased STAT-3 phosphorylation in Panc-1, and MiaPaCa2 tumor cell lines as well as the HP-DEV transformed pancreatic ductal cell line. Treatment with IL-6 resulted in increased Pim-1 protein expression in the Panc-1 but not the MiaPaCa2 parent cell lines. Induction of Pim-1 protein was also observed in both Panc-1 and MiaPaCa2 stably transfected over-expressing cell lines. Pre-treatment with the STAT-3 inhibitor cucurbitacin B resulted in inhibition of STAT-3 phosphorylation and decreased cell proliferation, but was not associated with suppression of Pim-1 protein expression in the Panc-1 cell lines. Over-expression of Pim-1 in the Panc-1 cell line was associated with no significant changes in basal apoptosis rate, cell growth rate in vitro or in flank xenografts, or IL-6 induced expression of VEGF. Conclusions: IL-6 stimulation activates both STAT-3 and Pim-1 kinase expression in pancreatic cell line models. Induction of Pim-1 kinase was cell line specific, suggesting that the molecular context is essential for this pathway to be activated. Suppression of STAT-3 with a pharmacological inhibitor resulted in exaggerated Pim-1 expression in over-expressing cell lines implying Pim-1 up-regulation may be one of the compensatory and/or stress pathways activated when STAT-3 is inhibited. Stable over-expressing Pim-1 kinase Panc-1 and MiaPaCa2 cells did not exhibit significant changes in growth or apoptosis, unlike previously reported studies in the literature with other pancreatic cancer cell line models. This may be due to the multiple pathways that are dysregulated in these cell lines. Both STAT-3 and Pim-1 kinase have previously been identified as drug targets in multiple malignancies, including leukemia, lymphoma, prostate, and pancreatic cancer. Our study suggests that both pathways may be activated in patients with elevated IL-6 levels. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2930. doi:10.1158/1538-7445.AM2011-2930
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