Core3 O-glycan synthase suppresses tumor formation and metastasis of prostate carcinoma PC3 and LNCaP cells through down-regulation of alpha2beta1 integrin complex.
Although there are numerous reports of carbohydrates enriched in cancer cells, very few studies have addressed the functions of carbohydrates present in normal cells that decrease in cancer cells. It has been reported that core3 O-glycans are synthesized in normal gastrointestinal cells but are down-regulated in cancer cells. To determine the roles of core3 O-glycans, we transfected PC3 and LNCaP prostate cancer cells with beta3-N-acetylglucosaminyltransferase-6 (core3 synthase) required to synthesize core3 O-glycans. Both engineered cell lines exhibited reduced migration and invasion through extracellular matrix components compared with mock-transfected cells. Moreover we found that alpha2beta1 integrin acquired core3 O-glycans in cells expressing core3 synthase with decreased maturation of beta1 integrin, leading to decreased levels of the alpha2beta1 integrin complex, decreased activation of focal adhesion kinase, and reduced lamellipodia formation. Upon inoculation into the prostate of nude mice, PC3 cells expressing core3 O-glycans produced much smaller tumors without metastasis to the surrounding lymph nodes in contrast to robust tumor formation and metastasis seen in mock-transfected PC3 cells. Similarly LNCaP cells expressing core3 O-glycans barely produced subcutaneous tumors in contrast to robust tumor formation by mock-transfected LNCaP cells. These findings indicate that addition of core3 O-glycans to beta1 and alpha2 integrin subunits in prostate cancer cells suppresses tumor formation and tumor metastasis.
Lee
Seung Ho
SH
From the Glycobiology Unit, Tumor Microenvironment Program, Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037.
Hatakeyama
Shingo
S
From the Glycobiology Unit, Tumor Microenvironment Program, Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037.
Yu
Shin-Yi
SY
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
Bao
Xingfeng
X
From the Glycobiology Unit, Tumor Microenvironment Program, Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037.
Ohyama
Chikara
C
Department of Urology, Hirosaki University School of Medicine, Hirosaki 036-2562, Japan.
Khoo
Kai-Hooi
KH
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
Fukuda
Michiko N
MN
From the Glycobiology Unit, Tumor Microenvironment Program, Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037.
Fukuda
Minoru
M
From the Glycobiology Unit, Tumor Microenvironment Program, Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037. Electronic address: minoru@burnham.org.
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary; D011554:Pseudopodia / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous
D017931:DNA Primers; D038982:Integrin alpha2beta1; D011134:Polysaccharides; D011994:Recombinant Proteins; D017351:N-Acetylglucosaminyltransferases