Abstract
Downregulation of integrins α3β1 and α5β1 strongly decreased cell colony formation and in vitro invasion and markedly enhanced anoikis in SK-Mel-147 human melanoma cells. These modifications were accompanied by a marked increase in the levels of active Akt protein kinase, which indicated it played a non-canonical function in the melanoma cells. Pharmacological inhibition of Akt1, an Akt isozyme, in cells depleted of α3β1 or α5β1 restored their invasive activity, while inhibition of the Akt 2 isoform did not cause a visible effect. Similar to our previous results with the α2β1 integrin, this finding suggested that in signaling pathways initiated by α3β1 and α5β1, the Akt1 isoform performs a non-canonical function in regulating invasive phenotype of melanoma cells. In contrast, when the effects of Akt inhibitors on anoikis of the melanoma cells were compared, the Akt2 isoform demonstrated a non-canonical activity in which Akt2 suppression led to a significant attenuation of apoptosis in cells with downregulated α3β1 or α5β1. Our results were the first evidence that, in the same tumor cells, different integrins can control various manifestations of tumor progression through distinct signaling pathways that are both common to various integrins and specific to a particular receptor.
Highlights
A hallmark of tumor progression is the ability of tumor cells to survive and grow in the absence of contact with the extracellular matrix
We have previously shown that α2β1 controls the invasion and anoikis of human SK-Mel-147 melanoma cells through a mechanism based on the non-canonical activity of Akt1, one of three Akt protein kinase isozymes, which demonstrated its function in suppressing invasion and promoting anoikis in melanoma cells [19, 20]
The ability of tumor cells to overcome anoikis is largely determined by the cell surface molecules, which include integrins
Summary
A hallmark of tumor progression is the ability of tumor cells to survive and grow in the absence of contact with the extracellular matrix (substrate). We have previously shown that α2β1 controls the invasion and anoikis of human SK-Mel-147 melanoma cells through a mechanism based on the non-canonical activity of Akt1, one of three Akt protein kinase isozymes, which demonstrated its function in suppressing invasion and promoting anoikis in melanoma cells [19, 20].
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