Th. Lee et al., Tamoxifen induces p21(WAF1) and p27(KIP1) expression in estrogen receptor-negative lung cancer cells, ONCOGENE, 18(29), 1999, pp. 4269-4274
Tamoxifen (Tam), besides its action as an anti-estrogen, also inhibits cell
proliferation of estrogen receptor (ER)negative cancer cells by an unknown
mechanism. In this study, we used ER-negative lung cancer cells to clarify
such ER-independent inhibitory effect of Tam, We found that Tam induced G1
growth arrest in these cells. However, our results indicated that the expr
ession of G1 cyclins (including D1, 2, 3 and E) was not regulated by Tam in
these lung cancer cells, Additionally, the protein levels of G1 acting cyc
lin-dependent kinases (CDKs), CDK2, 4 and 6, was unaltered in Tam-treated l
ung cancer cells with the exception of CDK2 expression in H322 cells which
was attenuated by Tam in a cell line-specific manner. We next examined the
effect of Tam on the expression of cyclin-dependent kinase inhibitors (CDKI
s) and our results demonstrated that the expression of p21(WAF1) and p27(KI
P1), but not p57(KIP2), was strongly activated by Tam in these cells. The a
mounts of p21(WAF1) and p27(KIP1) co-immunoprecipitated with cyclin E were
obviously increased after Tam treatment and reduced activity of cyclin E-as
sociated kinases and accumulation of hypo-phosphorylated retinoblastoma (Rb
) protein mere clearly detected in Tam-incubated cells. No consentaneous in
duction of CDKIs was found when ER-negative lung cancer cells were incubate
d with cytotoxic drugs, cisplatin and etoposide, this indicates that enhanc
ement of CDKI expression is not a non-specific effect of Tam, We also found
that Tam may up-regulate p21(WAF1) expression via transcription activation
. Considered together, these results suggest that Tam-induced growth inhibi
tion in ER-negative lung cancer cells is associated with induction of p21(W
AF1) and p27(KIP1).