title: α-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells.
abstract: PTEN dephosphorylates the 3-position phosphate of phosphatidylinositol 3,4,5 triphosphate (PIP(3)), thereby inhibiting AKT activation. Although attenuation of PTEN function has a major role in tumourigenesis, the underlying mechanisms remain unclear. Here we show that α-mannosidase 2C1 (MAN2C1) inhibits PTEN function in prostate cancer (PC) cells and is associated with a reduction in PTEN function in primary PC. MAN2C1 activates AKT and promotes the formation of PTEN-positive DU145 cell-derived xenograft tumours by imparing endogenous PTEN function. In 659 PC patients who were examined, ~60% of tumours were PTEN positive with elevated AKT activation. Of these, 80% display MAN2C1 overexpression that co-localizes with PTEN. Increases in MAN2C1 were detected only in PTEN-positive prostatic intraepithelial neoplasia and carcinomas, and showed a significant association with PC recurrence only in patients with PTEN-positive PCs. Mechanistically, MAN2C1 binds PTEN thereby inhibiting its PIP(3) phosphatase activity. These findings show that MAN2C1 function as a PTEN-negative regulator in PC cells.
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 4A6.
authors.forename: Lizhi
authors.initials: L
authors.lastname: He
authors.forename: Catherine
authors.initials: C
authors.lastname: Fan
authors.forename: Anil
authors.initials: A
authors.lastname: Kapoor
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ingram
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Rybak
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.forename: Jeffery
authors.initials: J
authors.lastname: Dickhout
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Cutz
authors.forename: James
authors.initials: J
authors.lastname: Scholey
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
mesh_terms: D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D043323:alpha-Mannosidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D043323:alpha-Mannosidase