Overexpression of membrane glycoprotein PC-1 in MDA-MB231 breast cancer cells is associated with inhibition of insulin receptor tyrosine kinase activity.
MDA-MB231 human breast cancer cells are unresponsive to insulin and contain a glycoprotein inhibitor of insulin-stimulated insulin receptor (IR) tyrosine kinase activity. Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients and transfected cells indicate that overexpression of membrane glycoprotein PC-1 reduces IR tyrosine kinase activity. In the present study, we measured PC-1 content and activity in MDA-MB231 and four other human breast cancer cell lines. We observed that PC-1 expression was 3- to 30-fold higher in MDA-MB231 cells when compared with the other breast cell lines. Wheat germ agglutinin extracts of MDA-MB231 cells inhibited IR tyrosine kinase activity. Treatment of these extracts with an antibody to PC-1 significantly reduced their ability to inhibit insulin-stimulated IR tyrosine kinase activity. In addition, when cell clones with different PC-1 activity were selected from MDA-MB231 cells, we found an inverse correlation (r = -0.741, P = 0.006) between the PC-1 activity and the insulin-stimulated IR autophosphorylation. A similar inverse correlation was observed in cell clones derived from the insulin-responsive breast cancer cell line MCF-7. By both immunoprecipitation and cross-linking studies we found PC-1 to be associated with IR. These studies indicate, therefore, that overexpression of PC-1 in MDA-MB231 cells may account, at least in part, for the reduced IR tyrosine kinase activity and suggest that PC-1 is a specific modulator of the IR activity in breast cancer cells.
Belfiore
A
A
Instituto di Medicina Interna, Endocrinologia e Malattie del Metabolismo, Università di Cantania, Ospedale Garibaldi, Italy, USA.
Costantino
A
A
Frasca
F
F
Pandini
G
G
Mineo
R
R
Vigneri
P
P
Maddux
B
B
Goldfine
I D
ID
Vigneri
R
R
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002457:Cell Extracts / Q000494:pharmacology; D002846:Chromatography, Affinity; D002999:Clone Cells; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation; D011755:Pyrophosphatases; D011972:Receptor, Insulin / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002457:Cell Extracts; D007328:Insulin; D008562:Membrane Glycoproteins; D011972:Receptor, Insulin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases