E-cadherin regulates anchorage-independent growth and survival in oral squamous cell carcinoma cells.
Integrin-basement membrane interactions provide essential signals that promote survival and growth of epithelial cells, whereas loss of such adhesions triggers programmed cell death. We found that HSC-3 human squamous carcinoma cells survived and grew readily as monolayers, but when they were suspended as single cells, they ceased proliferating and entered into the apoptotic death pathway, characterized by DNA fragmentation. In contrast, if the suspended carcinoma cells were permitted to form E-cadherin-mediated multicellular aggregates, they not only survived but proliferated. However, aggregated normal keratinocytes were unable to survive in suspension culture and rapidly became apoptotic. Anchorage independence and resistance to apoptosis of HSC-3 cell aggregates required high levels of extracellular Ca2+ and was inhibited with function-perturbing anti-E-cadherin antibody. Resistance to suspension-induced apoptosis in cell aggregates paralleled the up-regulation of Bcl-2 but occurred in the absence of focal adhesion kinase activation. Analysis of suspension-induced death in a set of cloned squamous epithelial cell lines with different levels of E-cadherin expression revealed that receptor-positive cell clones evaded apoptosis and proliferated in three-dimensional aggregate culture, whereas cadherin-negative clones failed to survive. Collectively, these observations indicate that cadherin-mediated intercellular adhesions generate a compensatory mechanism that promotes anchorage-independent growth and suppresses apoptosis.
Kantak
S S
SS
Department of Stomatology, Schools of Dentistry and Medicine, University of California, San Francisco, California 94143, USA.
Kramer
R H
RH
D015820:Cadherins / Q000276:immunology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division / Q000276:immunology / Q000502:physiology*; D002470:Cell Survival / Q000276:immunology / Q000502:physiology*; D053938:DNA Fragmentation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D009062:Mouth Neoplasms / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015820:Cadherins; D015815:Cell Adhesion Molecules; D019253:Proto-Oncogene Proteins c-bcl-2; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D002118:Calcium