Implication of alpha5beta1 integrin in invasion of drug-resistant MCF-7/ADR breast carcinoma cells: a role for MMP-2 collagenase.
Expression of alpha5beta1 integrin in the drug-resistant MCF-7/ADR breast carcinoma cells was inhibited by treatment of these cells with alpha5-specific siRNA. The decrease of alpha5beta1 expression resulted in a sharp decrease of expression of MMP-2 collagenase and inhibition of invasion activity of these cells in vitro. Similar decrease of invasion was also observed during inhibition of MMP-2 expression by treatment of these cells with MMP-2-specific siRNA. Inhibition of alpha5beta1 expression was also accompanied by significant decrease in cell content of active (phosphorylated) forms of signal protein kinases Akt and Erk1/2. Inhibition of activity of these kinases by treatment of cells with PI-3K/Akt-specific inhibitor LY294002 or Erk-specific inhibitor PD98059 resulted in inhibition of MMP-2 expression and the decrease of invasion in vitro. These data suggest that alpha5beta1 controls invasion ability of these cells by regulating expression of MMP-2, which involves PI-3K and Erk1/2 protein kinase signaling.
Morozevich
G E
GE
Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, 119121, Russia.
Kozlova
N I
NI
Cheglakov
I B
IB
Ushakova
N A
NA
Preobrazhenskaya
M E
ME
Berman
A E
AE
D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction
D039081:Integrin alpha5beta1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2