J. Cancer Mol. 3: 113-120, 2007
and Epidermal Growth Factor¡¦s Activation of Extracellular-Signal
Regulated Kinases 1/2 and DNA Synthesis Is Inhibited by Four Cardiac
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
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).
phosphorylation of ERK 1/2 was measured with Western blots, while DNA
synthesis was measured by bromodeoxyuridine incorporation.
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.
Four endogenous cardiac hormones inhibit EGF and insulin-stimulated ERK
1/2 and DNA synthesis, which may be important for their anti-cancer
ERK; mitogens; EGF; insulin; natriuretic peptides)___________________________________________________________________________
Received 5/8/07; Revised 7/26/07; Accepted 7/29/07.
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:
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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