title: Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis.
abstract: Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 N-acetylglucosaminyltransferase-L (C2GnT-L/GCNT1). This property allows androgen-refractory prostate cancer cells to evade galectin-1 (LGALS1)-induced apoptosis, but the mechanism is not known. We have recently reported that Golgi targeting of glycosyltransferases is mediated by golgins: giantin (GOLGB1) for C2GnT-M (GCNT3) and GM130 (GOLGA2)-GRASP65 (GORASP1) or GM130-giantin for core 1 synthase. Here, we show that for Golgi targeting, C2GnT-L also uses giantin exclusively whereas ST3Gal1 uses either giantin or GM130-GRASP65. In addition, the compact Golgi morphology is detected in both androgen-sensitive prostate cancer and normal prostate cells, but fragmented Golgi and mislocalization of C2GnT-L are found in androgen-refractory cells as well as primary prostate tumors (Gleason grade 2-4). Furthermore, failure of giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and C2GnT-L from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of non-muscle myosin IIA (MYH9) motor protein frees up Rab6a GTPase to promote phosphorylation of giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of C2GnT-L. Finally, the Golgi relocation of C2GnT-L in androgen-refractory cells results in their increased susceptibility to galectin-1-induced apoptosis by replacing sialyl-T antigen with polylactosamine.
  
  
  CONCLUSIONS
  This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis.
authors.affiliation: Nebraska Western Iowa Health Care System, Veteran Affairs Research Service, Omaha, Nebraska. Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Armen
authors.initials: A
authors.lastname: Petrosyan
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Holzapfel
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: David E
authors.initials: DE
authors.lastname: Muirhead
authors.affiliation: Nebraska Western Iowa Health Care System, Veteran Affairs Research Service, Omaha, Nebraska. Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. pcheng@unmc.edu.
authors.forename: Pi-Wan
authors.initials: PW
authors.lastname: Cheng
mesh_terms: D017209:Apoptosis; D001324:Autoantigens / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D037483:Galectin 1 / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism*; D000077614:Golgi Matrix Proteins; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009077:Mucins / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012799:Sialyltransferases / Q000378:metabolism*; D013379:Substrate Specificity; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D001324:Autoantigens; C108705:GORASP1 protein, human; D037483:Galectin 1; D000077614:Golgi Matrix Proteins; C097741:Golgin subfamily A member 2; C445499:LGALS1 protein, human; D008565:Membrane Proteins; D009077:Mucins; C087574:macrogolgin; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human
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