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.
Masuda
A
A
Divisions of Molecular Oncology and Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Osada
H
H
Yatabe
Y
Y
Kozaki
K
K
Tatematsu
Y
Y
Takahashi
T
T
Hida
T
T
Takahashi
T
T
Takahashi
T
T
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016373:DNA, Antisense / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016193:G1 Phase; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007532:Isoleucine / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D003470:Culture Media; D016373:DNA, Antisense; D008869:Microtubule-Associated Proteins; D009841:Oligonucleotides; D025521:Tumor Suppressor Proteins; D007532:Isoleucine; D050760:Cyclin-Dependent Kinase Inhibitor p27