Hypoxia-induced vascular endothelial growth factor transcription and protection from apoptosis are dependent on alpha6beta1 integrin in breast carcinoma cells.
The alpha6beta1 integrin has been implicated in breast carcinoma progression, but the mechanisms involved remain elusive. MDA-MB-435 cells engineered to be deficient in alpha6beta1 expression form primary tumors that are highly apoptotic and unable to metastasize, although they exhibit no increased apoptosis in vitro under standard culture conditions. Based on the hypothesis that alpha6beta1 is necessary for the survival of these cells in the tumor microenvironment, we report here that hypoxia protects these cells from apoptosis induced by serum deprivation and that hypoxia-mediated protection requires alpha6beta1 expression. We investigated the influence of alpha6beta1 on vascular endothelial growth factor (VEGF) expression because autocrine VEGF is necessary for the survival of serum-deprived cells in hypoxia. The results obtained indicate that alpha6beta1 is necessary for VEGF expression because the ability of hypoxia to activate HIF-1 and to stimulate VEGF transcription in MDA-MB-435 cells is dependent on alpha6beta1 expression by a mechanism that involves protein kinase C-alpha.
Chung
Jun
J
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Yoon
Sangoh
S
Datta
Kaustubh
K
Bachelder
Robin E
RE
Mercurio
Arthur M
AM
D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039121:Integrin alpha6beta1 / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D051571:Protein Kinase C-alpha; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039121:Integrin alpha6beta1; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha