Sh. Wang et al., Susceptibility of thyroid cancer cells to 7-hydroxystaurosporine-induced apoptosis correlates with Bcl-2 protein level, THYROID, 11(8), 2001, pp. 725-731
7-Hydroxystaurosporine (UCN-01) is a selective protein kinase C (PKC) inhib
itor and is being developed as a novel anticancer agent. Because of reports
that PKC may be involved in the pathogenesis of some forms of thyroid canc
ers, we examined four thyroid carcinoma lines (FRO, KAT5, NPA, and WRO). Th
ese cells were found to have different susceptibility to UCN-01 treatment,
and there appeared to be a correlation between UCN-01-induced death and exp
ression levels of endogenous Bcl-2. KAT5 cells, which normally express a lo
w amount of Bcl-2, exhibited significantly higher sensitivity to UCN-01-ind
uced death than the other cell lines. Of interest, susceptibility did not r
elate to PKC activity or its inhibition by UCN-01. In order to investigate
the role of Bcl-2 in UCN-01-induced death, KAT5 cells were transfected to o
verexpress Bcl-2. KAT5/Bcl-2 cells were capable of conferring resistance to
UCN-01-induced death. Furthermore, upregulating of Bcl-2 by 1 alpha ,25-di
hydroxyvitamin D3 (VD3) could protect primary thyroid cell from death induc
ed by UCN-01. Both in situ TUNEL staining and the flow cytometric analysis
of cytokeratin-18 (CK18) cleavage confirmed that UCN-01 was indeed inducing
apoptosis, and that this effect was inhibited by increased expression of B
cl-2. These results suggest that the Bcl-2 can block the UCN-01-activated c
ell death pathway and that the expression of Bcl-2 is inversely related to
thyroid carcinoma cell susceptibility to UCN-01. Therefore, the analysis of
the expression of apoptosis suppressors provides a basis for the use of UC
N-01 in the treatment of thyroid cancer.