Ghrelin and a novel preproghrelin isoform are highly expressed in prostate cancer and ghrelin activates mitogen-activated protein kinase in prostate cancer.
OBJECTIVE
There is evidence that the hormone ghrelin stimulates proliferation in the PC3 prostate cancer cell line although the underlying mechanism(s) remain to be determined. A novel, exon 3-deleted preproghrelin isoform has previously been detected in breast and prostate cancer cells; however, its characterization, expression, and potential function in prostate cancer tissues are unknown.


METHODS
Expression of ghrelin and exon 3-deleted preproghrelin was investigated in prostate cancer cell lines and tissues by reverse transcription-PCR and immunohistochemistry. Proliferation and apoptosis assays were done in the LNCaP prostate cancer cell line to determine if ghrelin stimulates proliferation and/or cell survival. Stimulation of mitogen-activated protein kinase (MAPK) pathway activation by ghrelin was determined in PC3 and LNCaP cells by immunoblotting with antibodies specific for phosphorylated MAPKs.


RESULTS
Prostate cancer tissues display greater immunoreactivity for ghrelin and exon 3-deleted preproghrelin than normal prostate tissues, and prostate cancer cell lines secrete mature ghrelin into conditioned medium. Treatment with ghrelin (10 nmol/L), but not the unique COOH-terminal peptide derived from exon 3-deleted preproghrelin, stimulates proliferation in the LNCaP cells (45.0 +/- 1.7% above control, P < 0.01) and rapidly activates the extracellular signal-regulated kinase-1/2 MAPK pathway in both PC3 and LNCaP cell lines. Ghrelin, however, does not protect prostate cancer cells from apoptosis induced by actinomycin D (1 microg/mL). The MAPK inhibitors PD98059 and U0126 blocked ghrelin-induced MAPK activation, as well as proliferation, in both cell lines.


CONCLUSIONS
These data suggest that these components of the ghrelin axis may have potential as novel biomarkers and/or adjunctive therapeutic targets for prostate cancer.
Yeh
Anthony H
AH
Authors' Affiliation: School of Life Sciences, Queensland University of Technology, Brisbane, Australia.
Jeffery
Penelope L
PL
Duncan
Russell P
RP
Herington
Adrian C
AC
Chopin
Lisa K
LK
D017209:Apoptosis; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D004789:Enzyme Activation / Q000187:drug effects; D005091:Exons / Q000235:genetics; D054439:Ghrelin; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009037:Motilin / Q000235:genetics*; D010446:Peptide Fragments / Q000494:pharmacology; D036361:Peptide Hormones / Q000235:genetics* / Q000494:pharmacology*; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D054439:Ghrelin; D010446:Peptide Fragments; D036361:Peptide Hormones; D009037:Motilin; D020928:Mitogen-Activated Protein Kinases