Open Accessp16 INK4 Expression Is Associated with the Increased Sensitivity of Human Non‐small Cell Lung Cancer Cells to DNA Topoisomerase I Inhibitors
Author(s) -
Fukuoka Kazuya,
Adachi Junichi,
Nishio Kazuto,
Arioka Hitoshi,
Kurokawa Hirokazu,
Fukumoto Hisao,
Ishida Tomoyuki,
Nomoto Taisuke,
Yokote Hideyuki,
Tomonari Akira,
Narita Nobuhiro,
Yokota Jun,
Saijo Nagahiro
Publication year - 1997
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.1997.tb00322.x
Subject(s) - biology , topoisomerase , microbiology and biotechnology , ectopic expression , cell culture , cancer research , dna , biochemistry , genetics
Inactivation of p16 INK4 , an inhibitor of cyclin‐dependent kinases 4 (CDK4) and 6 (CDK6), may be essential for ontogenesis in non‐small cell lung cancer (NSCLC). We examined the sensitivity of two clones of P16 INK4 ‐transfected NSCLC cell line with homozygous deletion of p16 INK4 , A549/pl6‐l and 2, to DNA topoisomerase I (topo I) inhibitors. A549/pl6‐l and ‐2 showed 7.7‐ and 9.1‐fold increases in sensitivity to CPT‐11 (11,7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin), respectively, compared with A549 cells. Ectopic p16 INK4 ‐expressing cells also showed ∼4.0‐fold increase in sensitivity to SN‐38 (7‐ethyl‐10‐hydroxycamptothecin), the active metabolite of CPT‐11, compared to the parent cells. The topo I‐mediated DNA relaxation activities of ectopic p16 INK4 ‐expressing cells were approximately 5 times higher than those of the parent cells. Northern and western blot analyses indicate that these increased topo I activities of ectopic p16 INK4 ‐expressing cells were due to an elevated topo I mRNA level and an increase in topo I protein. The chemosensitivity to topo I inhibitors, topo I mRNA level, protein content and activity of a pl6 INK4 revertant, lacking functional p16 INK4 , tended to be restored toward those of the parental phenotype to some extent. These results suggest that p16 1NK4 expression is closely associated with the increased sensitivity of ectopic pl6 INK4 ‐expressing NSCLC cells to topo I inhibitors. The up‐regulation of topo I mRNA level, protein content and activity may he responsible for this hypersensitivity.