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Yeh AH, Jeffery PL, Duncan RP, Herington AC, Chopin LKGhrelin and a novel preproghrelin isoform are highly expressed in prostate cancer and ghrelin activates mitogen-activated protein kinase in prostate cancer. Clin Cancer Res 11: 8295-8303

Authors' Affiliation: School of Life Sciences, Queensland University of Technology, Brisbane, Australia.
Clinical Cancer Research (Impact Factor: 8.19). 12/2005; 11(23):8295-303. DOI: 10.1158/1078-0432.CCR-05-0443
Source: PubMed

ABSTRACT 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.
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.
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.
These data suggest that these components of the ghrelin axis may have potential as novel biomarkers and/or adjunctive therapeutic targets for prostate cancer.

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    • "However, the ghrelin gene can also undergo additional processes of alternative splicing such as exon skipping or intron retention. Specifically, an event of exon 3 skipping has been documented (Yeh et al. 2005), which generates a 91-amino acid peptide named the Ex3-deleted ghrelin that lacks the coding region for obestatin (Fig. 1). Although the precise functions of the Ex3-deleted ghrelin variant remain uncertain, its expression is increased in human prostate and breast cancers (Seim et al. 2009), suggesting a putative role in these pathologies. "
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    • "These results could in part account for the high obestatin concentrations detected in human semen samples (Moretti et al., 2011). Studies have reported that prostate cancer and prostate cancer cell lines are able to produce ghrelin (Yeh et al., 2005); however, according to our findings, normal prostate cells fail to express this hormone. Finally, ghrelin and obestatin were detected by immunofluorescence in ejaculated human spermatozoa. "
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    • "As prostate cancer cell lines produce ghrelin, and exogenous ghrelin treatment stimulates cell proliferation in prostate cancer cell lines, we hypothesized that the ghrelin axis may play an autocrine/paracrine role in prostate cancer [39]. Our previous studies demonstrated that ghrelin and the ghrelin receptor, GHSR, are expressed at the mRNA and protein levels in prostate cancer cell lines and prostate cancer specimens [16,38,39]. A study demonstrating that a fluorescein-labelled ghrelin (1–18) probe binds prostate cancer tissue with high specificity also demonstrated GHSR1a expression in the PC3 and LNCaP prostate cancer cell lines and the BPH-1 cell line [20]. "
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