Ghrelin and a Novel Preproghrelin Isoform Are Highly Expressed in Prostate Cancer and Ghrelin Activates Mitogen-Activated Protein Kinase in Prostate Cancer

• Published in: Clinical cancer research Vol. 11; no. 23; pp. 8295 - 8303
• Main Authors: YEH, Anthony H, JEFFERY, Penelope L, DUNCAN, Russell P, HERINGTON, Adrian C, CHOPIN, Lisa K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2005
• Subjects: Antineoplastic agents; Apoptosis; Biological and medical sciences; Cell Proliferation; Culture Media, Conditioned; Enzyme Activation - drug effects; Exon 3–deleted preproghrelin; Exons - genetics; Ghrelin; Growth hormone secretagogue receptor (GHS-R); Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Mitogen-Activated Protein Kinase (MAPK); Mitogen-Activated Protein Kinases - metabolism; Motilin - genetics; Nephrology. Urinary tract diseases; Peptide Fragments - pharmacology; Peptide Hormones - genetics; Peptide Hormones - pharmacology; Pharmacology. Drug treatments; Prostate cancer; Prostatic Hyperplasia - enzymology; Prostatic Hyperplasia - genetics; Prostatic Hyperplasia - pathology; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Sequence Deletion; Tumor Cells, Cultured; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Molecular form; Urinary system disease; Prostate disease; Enzyme; Ghrelin; Mitogen-activated protein kinase; Malignant tumor; Gene expression; Male genital diseases; Prostate cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0443

Purpose: 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.
Experimental Design: 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 μg/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.