title: Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling.
abstract: Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer.
authors.affiliation: Department of Urology, Miyagi Cancer Center, Natori, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kawamura
authors.forename: I
authors.initials: I
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: K
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: S
authors.initials: S
authors.lastname: Ueno
authors.forename: H
authors.initials: H
authors.lastname: Aoki
authors.forename: T
authors.initials: T
authors.lastname: Tochigi
authors.forename: M
authors.initials: M
authors.lastname: Kuwahara
authors.forename: T
authors.initials: T
authors.lastname: Kitamura
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: S
authors.initials: S
authors.lastname: Moriya
authors.forename: T
authors.initials: T
authors.lastname: Miyagi
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018450:Disease Progression; D051765:Early Growth Response Transcription Factors / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000728:Androgens; D051765:Early Growth Response Transcription Factors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C465436:Neu3 protein, human; D009439:Neuraminidase; D017430:Prostate-Specific Antigen