Antagonism of endogenous growth hormone-releasing hormone (GHRH) leads to reduced proliferation and apoptosis in MDA231 breast cancer cells.
GHRH, in addition to stimulating the release of growth hormone (GH) from the pituitary, is a trophic factor for pituitary somatotrophs. Growth hormone-releasing hormone is also expressed in the gonads, gastrointestinal tract, pancreas, thymus, and lymphocytes, as well as in tumors of the pancreas, lung, central nervous system, and breast. Since GHRH has mitogenic effects, we examined the hypothesis that GHRH is an autocrine/paracrine growth factor in neoplastic breast tissue. The effect of disrupting endogenous GHRH on cell growth and apoptosis of MDA231 cells was examined through the use of a competitive GHRH antagonist, [N-acetyl-Tyr1, D-Arg2] fragment 1-29Amide (GHRHa). Cell proliferation was determined by direct cell counting and tritiated thymidine incorporation. Apoptosis was analyzed by examination of DNA laddering and nuclear condensation. GHRHa resulted in a dose-dependent, transient, and reversible decrease in cell number, proliferation rate, and tritiated thymidine uptake. Conversely, GHRHa led to a marked and dose-dependent increase in both DNA laddering and nuclear condensation. These results indicate that disruption of endogenous GHRH action in MDA231 cells results in both decreased cellular proliferation and increased apoptosis. Taken together, the findings suggest that endogenous GHRH acts as an autocrine/paracrine factor in the regulation of growth of at least some breast cancer cell types.
Zeitler
Philip
P
Department of Pediatrics, University of Colorado Health Science Center, and The Children's Hospital, Denver 80218, USA. Phil.Zeitler@uchsc.edu
Siriwardana
Gamini
G
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D002467:Cell Nucleus / Q000648:ultrastructure; D053938:DNA Fragmentation; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology; D017337:Sermorelin; D014407:Tumor Cells, Cultured
C470407:(N-acetyl-tyr1,D-arg2)fragment 1-29 amide; D010446:Peptide Fragments; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone