J. Cancer Mol. 3: 113-120, 2007

[Research Paper]

Insulin and Epidermal Growth Factor’s Activation of Extracellular-Signal Regulated Kinases 1/2 and DNA Synthesis Is Inhibited by Four Cardiac Hormones

Ying Sun, Ehrentraud J. Eichelbaum, Hai Wang, and David L. Vesely

Departments of Internal Medicine, Molecular Pharmacology and Physiology, University of South Florida Cardiac Hormone Center and James A. Haley Veterans Medical Center, Tampa, FL, USA; Department of Interdisciplinary Oncology, Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Abstract:

  AIM: This study is to determine if four endogenous growth inhibitors (i.e. four cardiac hormones) can inhibit the activity of extracellular-signal regulated kinases 1/2 (ERK 1/2) stimulated by endogenous growth promoters i.e. insulin and epidermal growth factor (EGF).

METHODS: The phosphorylation of ERK 1/2 was measured with Western blots, while DNA synthesis was measured by bromodeoxyuridine incorporation.

RESULTS: These four peptide hormones, i.e. vessel dilator, kaliuretic peptide, long acting natriuretic peptide, and atrial natriuretic peptide decreased insulin’s (10 mM) 66% enhanced phosphorylation in human prostate adenocarcinoma cells to 10%, 8%, 24%, and 13% above non-stimulated ERK 1/2 activity, respectively.  The EGF’s (50 ng/ml) 66% enhanced phosphorylation of ERK 1/2 in human prostate cancer cells was inhibited to -11% (i.e. 117% decrease), 4%, 13% and 16% by vessel dilator, atrial natriuretic peptide, long acting natriuretic peptide, and kaliuretic peptide compared to non-stimulated ERK 1/2 activity, respectively.  In human pancreatic cancer cells insulin and epidermal growth factor stimulated ERK 1/2 to a larger extent, i.e., 98% and 472%, respectively, and this stimulation was decreased to below baseline by the four cardiac hormones.  Respective antibodies to these four cardiac hormones blocked their ability to inhibit the ERK 1/2 phosphorylation and DNA synthesis induced by insulin and epidermal growth factor, indicating that their effects are specific.

CONCLUSION: Four endogenous cardiac hormones inhibit EGF and insulin-stimulated ERK 1/2 and DNA synthesis, which may be important for their anti-cancer effects.

(Keywords: ERK; mitogens; EGF; insulin; natriuretic peptides)___________________________________________________________________________

Received 5/8/07; Revised 7/26/07; Accepted 7/29/07.

¹Correspondence: Dr. David L. Vesely, Departments of Medicine, Molecular Pharmacology and Physiology, USF Cardiac Hormone Center, J. A. Haley Veterans Medical Center-151, 13000 Bruce B. Downs Blvd., Tampa, Florida 33612, USA. Phone: 1-813-9727624. Fax: 1-813-9727623. E-mail: david.vesely@med.va.gov

²Abbreviations: EGF, epidermal growth factor; ERK 1/2, extracellular-signal regulated kinases 1 and 2; MAPK, mitogen-activated protein kinase; LANP, long acting natriuretic peptide; VDL, vessel dilator; KP, kaliuretic peptide; ANP, atrial natriuretic peptide; BrdU, bromodeoxyuridine; NPR, natriuretic peptide receptors.

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