Anoikis is defined as apoptosis, which is induced by inappropriate cell-matrix interactions.
Cancer cells with anoikis resistance tend to undergo
metastasis, and this phenomenon has been reported to be associated with
integrin and FAK activity.
HPW-RX40 is a derivative of 3,4-methylenedioxy-β-nitrostyrene, which is known to prevent platelet aggregation by inhibition of
integrin. In the present study, we investigated the effect of
HPW-RX40 on an anoikis-resistant human
breast cancer cell line MDA-MB-231.
HPW-RX40 inhibited cell aggregation and induced cell death in suspending MDA-MB-231 cells, but had only little effect on the monolayer growth of adherent cells. Analysis of
caspase activation and
poly (ADP-ribose) polymerase (PARP) cleavage confirmed anoikis in HPW-RX40-treated suspending
cancer cells.
HPW-RX40 also affected the Bcl-2 family
proteins in detached
cancer cells. Furthermore,
HPW-RX40 inhibited detachment-induced activation of FAK and the downstream phosphorylation of Src and
paxillin, but did not affect this pathway in adherent
cancer cells. We also found that the expression and activation of β1
integrin in MDA-MB-231 cells were reduced by
HPW-RX40. The combination of
HPW-RX40 with an EGFR inhibitor led to enhanced anoikis and inhibition of the FAK pathway in
breast cancer cells. Taken together, our results suggest that
HPW-RX40 restores the anoikis sensitivity in the metastatic
breast cancer cells by inhibiting
integrin and subsequent FAK activation, and reveal a potential strategy for prevention of
tumor metastasis.