The modulation of the activity of extracellular signal-regulated kinases (ERKs) 1/2 by endogenous growth promoters such as insulin or epidermal growth factor (EGF) and endogenous growth inhibitors provides a potential means of regulating cancer cell growth. We determined the effect of four cardiac peptide hormones with significant anticancer effects in human breast, colon, pancreatic, kidney, and prostate adenocarcinomas for their ability to inhibit insulin and EGF's ability to enhance the phosphorylation of ERK 1/2 in human prostate adenocarcinoma cells. These four peptide hormones, that is, vessel dilator (VDL), kaliuretic peptide (KP), long-acting natriuretic peptide (LANP), and atrial natriuretic peptide, decreased insulin's enhanced 66% phosphorylation down to 10%, 8%, 24%, and 13% above nonstimulated ERK 1/2 activity. EGF's 66% enhanced phosphorylation of extracellular signal-regulated kinase 1/2 was inhibited to minus 11% (ie, 117% decrease), plus 4%, 13%, and 16% by VDL, ANP, LANP, and KP compared with nonstimulated EGF activity, respectively. Using the respective antibodies to these for cardiac hormones completely blocked their ability to inhibit the phosphorylation of ERKs by insulin and EGF, indicating that their effects are specific. Our results indicate that there are four endogenous cardiac hormones that inhibit EGF and insuli- stimulated ERKs. These data suggest that the ability of these four cardiac hormones to inhibit mitogen (EGF and insulin)-stimulated ERK 1/2 may be important for their anticancer actions.
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