Protective function of p27 ^KIP1 against apoptosis in small cell lung cancer cells in unfavorable microenvironments

A previous study of ours unexpectedly found that in contrast to frequent reductions in non-small cell lung cancer, high expression of the p27 ^KIP1 cyclin-dependent kinase (CDK) inhibitor was retained in virtually all small cell lung cancers (SCLCs), suggesting the possibility of high expression of nonfunctional p27 ^KIP1 in this virulent tumor. The study presented here, however, shows that p27 ^KIP1 in SCLC biochemically functions as a CDK inhibitor, clearly showing induction apparently associated with G ₁ /G ₀ arrest and efficient binding to and inhibition of the cyclin E-CDK2 complex. Interestingly, induction of p27 ^KIP1 seems to confer on SCLC cells the ability to survive under culture conditions unfavorable for cell growth such as a lack of nutrients and hypoxia. Subsequent experiments manipulating p27 ^KIP1 levels by using a sense p27 ^KIP1 expression construct or an antisense oligonucleotide supported this notion. These observations suggest that high expression of p27 ^KIP1 in vivo may favor the survival of SCLC by preventing apoptosis in a microenvironment unfavorable for cell proliferation.