Mitogenic and anti-apoptotic actions of adipocyte-derived hormone leptin in prostate cancer cells.
OBJECTIVE
To investigate the proliferative and anti-apoptotic effects of leptin on human prostate cancer cells, and the role of related signalling pathways in mediating these actions, as obesity is a possible risk factor for prostate cancer and leptin, an adipocyte-derived hormone, has mitogenic action in various cell types.


METHODS
Two human prostate cancer cell lines, DU145 and PC-3, were treated with leptin (5-100 ng/mL) for up to 48 h. Under serum-free conditions, cell proliferation was measured using a colorimetric tetrazolium assay and apoptosis by an enzyme-linked immunosorbent assay measuring cell death. Also, the phosphorylation of ERK1/2 and Akt was detected by Western blotting, and specific inhibitors of mitogen-activated protein kinase (MAPK) (PD98059; 40 microm) and phosphatidylinositol 3-kinase (PI3-K, LY294002; 40 microm) were used to evaluate the role of these signalling pathways.


RESULTS
Leptin dose-dependently increased the cell number in both cell lines for up to 48 h of incubation, the mean (sem) percentage of the control being 189 (4.3)% for DU145 and 173 (7.5)% for PC-3 (100 ng/mL leptin, 48 h; P < 0.01). Leptin also significantly reduced the number of apoptotic cells after 24 h of treatment, dose-dependently caused ERK1/2 and Akt phosphorylation; pretreatment with inhibitors of MAPK and PI3-K inhibited these responses.


CONCLUSIONS
These results show that chronic increases in leptin might enhance the growth of prostate cancer via the MAPK and PI3-K pathways. Further studies are needed to investigate whether the ability of leptin to stimulate mitogenic/anti-apoptotic signal transduction pathways could represent a target for anticancer drug discovery.
Hoda
M Raschid
MR
Department of Urology, Helios Clinics Berlin-Buch, University Medical School of Charité, Berlin, Germany. rhoda@ucsd.edu
Popken
Gralf
G
D017667:Adipocytes / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009765:Obesity / Q000150:complications*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000209:etiology / Q000473:pathology*; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases