title: Long‑term exposure to leptin enhances the growth of prostate cancer cells.
abstract: Obesity correlates with an increased risk of developing prostate cancer (PCa) and leptin plays an important role in PCa progression. Since leptin is produced by adipocytes, the serum leptin level is higher in obese than in non-obese individuals. However, the effects of leptin remain controversial and unclear. The aim of the present study was to investigate the effect of leptin on PCa cell aggressiveness. Three human PCa cell lines (LNCaP, DU145 and PC-3) were treated with recombinant leptin for 28 days. Cell proliferation, migration, and invasion were estimated using the WST assay, a wound-healing assay, and a BD Matrigel invasion assay, respectively. The mechanism underlying the proliferative effect of leptin was investigated by cell transfections with small interfering RNA (siRNA) against the leptin receptor (ObR) or forkhead box O1 (FOXO1), and by immunocytochemistry. Long-term exposure of PCa cells to leptin enhanced their proliferation, migration and invasion. Leptin increased ObR expression and enhanced Akt phosphorylation constitutively. Leptin also increased the phosphorylation of FOXO1 via PI3K signaling and FOXO1 gene silencing enhanced PCa cell proliferation. Leptin induced the translocation of FOXO1 from the nucleus to the cytoplasm. Furthermore, the PI3K inhibitor, LY294002 suppressed this translocation. These results suggested that leptin regulated the subcellular localization of FOXO1 and induced Akt phosphorylation. Additionally, we revealed that leptin increased the expression of cyclin D1 and decreased the expression of p21 protein. In conclusion, long-term exposure to leptin increased the cell proliferation, migration, and invasion of PCa cells through inactivation of FOXO1. This inactivation resulted from exclusion of FOXO1 from the nucleus and its restriction to the cytoplasm through PI3K/Akt signaling. Our findings contribute to an understanding of the association between obesity and PCa aggressiveness.
authors.affiliation: Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.
authors.forename: Terutaka
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Kikugawa
authors.affiliation: Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Tanji
authors.affiliation: Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Miura
authors.affiliation: Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Asai
authors.affiliation: Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.affiliation: Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D020738:Leptin; D034741:RNA, Small Interfering; D054411:Receptors, Leptin