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Vol. 59, Issue 3, 593-603, March 2001
- and 
-Catenins and APC Protein in Paclitaxel-Induced Apoptosis
Kaplan Comprehensive Cancer Center, New York University
School of Medicine, New York, New York
Cell adhesion is important in the regulation of cell proliferation,
migration, survival, and apoptosis. The major components of cell
adhesion are the cadherin family of proteins, 
-, 
- and 
-catenins, and cytoskeletons. In addition, -catenin, when
associated with adenomatous polyposis coli (APC) protein, an
oncosuppressor, is implicated in the regulation of
-catenin/APC-related signaling pathways. To examine the correlation
between impairment of cell adhesion events and apoptosis, we used human
non-small-cell lung cancer H460 and H520 cell lines as models to
determine whether paclitaxel-induced apoptosis is associated with
disruption of the components of cell adhesion and their functions.
Paclitaxel treatment resulted in cells rounding up and losing contact
with their neighboring cells, suggesting that the drug does indeed affect cell adhesion and related events. Western blot analysis revealed
that paclitaxel caused a time- and concentration-dependent cleavage of
-catenin, -catenin, and APC protein, but not -catenin or
E-cadherin. These cleavages of -catenin and -catenin were apoptosis-dependent, not mitosis-dependent. Paclitaxel treatment led to
the proteolysis and activation of caspase-3 and -7, but not caspase-1.
Furthermore, paclitaxel-induced apoptosis and cleavage of -catenin
and -catenin were inhibited by the pan-caspase inhibitor Z-VAD-FMK
and partially inhibited by the caspase-3 inhibitor Z-DEVD-FMK but were
not affected by the caspase-1 inhibitor AC-YVAD-CMK. Although the
pan-caspase inhibitor blocked the cleavage of -catenin as well as
DNA fragmentation, it did not affect paclitaxel-induced M-phase arrest
and only partially prevented cell-growth inhibition. Biochemical
studies revealed that cleaved -catenin was detected only in the
Triton X-100 insoluble fraction, suggesting that it might localize in
nuclear and/or membrane structures. Interestingly, the
paclitaxel-induced -catenin fragment lost its ability to bind to
E-cadherin, -catenin, or APC protein and to serve as a substrate for
tyrosine kinase. All our data demonstrate that the caspase-mediated
cleavage of -catenin, -catenin, and APC protein might contribute
to paclitaxel-induced apoptosis.
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