Human melanoma cells expressing the alphavbeta3 integrin are partially protected from necrotic cell death induced by dynamic matrix detachment.
Anchorage-independence is a hallmark of metastatic cancer cells. In previous studies we characterized a novel model for anchorage-independence employing dynamic matrix detachment (DMD) using rotation in low shear stress conditions. We observed that in contrast to the classical apoptosis-inducing static matrix detachment (SMD) model, the venous circulation-mimicking DMD model induced necrosis in transformed cells. In the current study we revisited the mechanism of DMD-induced cell death and evaluated the contribution of alphavbeta3 integrin overexpression in human melanoma cells to anchorage-independence in DMD. DMD cell culture induced primarily necrosis in the melanoma cells studied. alphavbeta3, but not the control related alphaIIbbeta3 integrin, could confer survival advantage in DMD. While apoptosis was unaffected, constitutive, unligated alphavbeta3 overexpression was associated with attenuation of necrosis in DMD. alphavbeta3 overexpressing melanoma cells manifested AKT activation that was independent of DMD conditions. Furthermore, while a small molecular inhibitor of AKT phosphorylation induced apoptosis in adherent cells, in DMD conditions it had no effect on cell outcome. Thus, alphavbeta3-overexpressing melanoma cells are partially protected from DMD-induced cell death in an apoptosis-independent mechanism. This finding may be one of the factors accounting for anchorage-independence in circulating metastatic melanoma cells.
Tzukert
K
K
Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Shimony
N
N
Krasny
L
L
Urieli-Shoval
S
S
Gorodetsky
R
R
Avrahami
I
I
Nettelbeck
D M
DM
Haviv
Y S
YS
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D009336:Necrosis / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D039302:Integrin alphaVbeta3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt