Potent selective inhibition of STAT 3 versus STAT 1 by cardiac hormones Meghan L. Lane • Chelsea D. Frost • Jennifer P. Nguyen • William P. Skelton IV • Michelle Skelton • David L. Vesely Received: 30 April 2012 / Accepted: 25 August 2012 / Published online: 11 September 2012 Ó Springer Science+Business Media, LLC (outside the USA) 2012 Abstract Signal transducers and activators of transcription (STATs) are the final ‘‘switches’’ that activate gene expres- sion patterns that lead to human malignancy. Extracellular signal-regulated kinases (ERK 1/2) activate STAT 3; four cardiovascular hormones inhibit ERK 1/2 kinases, leading to the hypothesis that they may also inhibit STATs. These four cardiac hormones, i.e., vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP), eliminate human cancers growing in mice. These four cardiac hormones’ effects on STATs 1 and 3 were examined in human small-cell lung cancer and human pan- creatic adenocarcinoma cells. Vessel dilator, LANP, kaliu- retic peptide, and ANP maximally decreased STAT 3 by 88, 54, 55, and 65 %, respectively, at their 1 lM concentrations in human small-cell lung cancer cells and STAT 3 by 66, 57, 70, and 77 % in human pancreatic adenocarcinoma cells, respectively. The cardiac hormones (except LANP) also significantly decreased STAT 3 measured by Western blots. These cardiac hormones did not decrease STAT 1 in either human small-cell lung cancer or pancreatic adenocarcinoma cells. We conclude that these four cardiac hormones are significant inhibitors of STAT 3, but not STAT 1, in human small-cell lung cancer and pancreatic adenocarcinoma cells, which suggests a specificity for these hormones’ anticancer mechanism(s) of action enzymology in human cancer cells. Keywords Cardiac hormones Á Epidermal growth factor Á Extracellular signal-regulated kinases Á Signal transducers and activators of transcription Introduction Signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors [1, 2] that are logical targets for the treatment of human cancers [3]. These transcription factors are the final ‘‘switches’’ that activate the gene-expression patterns that lead to malignancy [1]. The STAT family of proteins has seven members identified in mammalian cells with STAT 3 being important in malignant transduction [1, 2, 4]. STAT 3 is overexpressed in a variety of human tumors [1, 5, 6]. Epidermal growth factor receptor-mediated growth of squamous carcinoma cells requires STAT 3, but not STAT 1 [5]. Targeting of STAT 3 is also a strategy for reversing cancer drug resis- tance as elevated constitutive expression of STAT 3 cor- relates with paclitaxel resistance [7]. Extracellular signal-regulated kinases (ERK) 1/2 acti- vate (i.e., phosphorylate) STAT 3 at serine 727 in response to growth factors and STAT 3 is an excellent substrate for M. L. Lane Á C. D. Frost Á M. Skelton Á D. L. Vesely (&) Departments of Medicine, Molecular Pharmacology and Physiology, USF Cardiac Hormone Center, James A. Haley VA Medical Center and University of South Florida, 13000 Bruce B. Downs Blvd, Tampa, FL 33612, USA e-mail: david.vesely@va.gov M. L. Lane e-mail: megja.vu@gmail.com C. D. Frost e-mail: cfrost@usf.edu.com M. Skelton e-mail: mskelton@gmail.com J. P. Nguyen Department of Biology, Wichita State University, Wichita, KS, USA e-mail: jennynguyen50@yahoo.com W. P. Skelton IV University of Florida College of Medicine, Gainesville, FL, USA e-mail: wskelton@gmail.com 123 Mol Cell Biochem (2012) 371:209–215 DOI 10.1007/s11010-012-1437-1