Down‐regulation of SKP2 induces apoptosis in lung‐cancer cells
Open Access
- 1 April 2003
- journal article
- Published by Wiley in Cancer Science
- Vol. 94 (4), 344-349
- https://doi.org/10.1111/j.1349-7006.2003.tb01444.x
Abstract
S-Phase kinase associated protein 2 (SKP2), an F-box protein constituting the substrate-recognition subunit of the SCFSKP2 ubiquitin ligase complex, targets cell-cycle regulators, such as the cyclin-de-pendent kinase inhibitor p27KIP1, for ubiquitin-mediated degradation. Our earlier studies indicated frequent amplification and over-expression of the SKP2 gene in primary small-cell lung cancers (SCLCs) and cell lines derived from this type of tumor, and showed that down-regulation of SKP2 expression by means of an antisense oligonucleotide inhibited the growth of SCLC cells in culture (Yokoi et al. Am J Pathol, 161, 207-216, 2002). The anti-sense effect was confirmed in two cell lines of non-small cell lung cancer (NSCLC) that also exhibited over-expression of the gene. In the work reported here, we examined the mechanism(s) responsible for antisense-mediated growth inhibition of SCLC- and NSCLC-derived cultures. SKP2-antisense treatment not only suppressed DNA synthesis, as determined by [3H]thymidine incorporation, but also induced spontaneous apoptosis characterized by an increase in the sub-G1 population, fragmentation of nuclei, and activation of caspase-3. Our results suggest that since down-regulation of SKP2 appears to induce apoptosis in lung-cancer cells directly, targeting this molecule could represent a promising new therapeutic approach for this type of cancer, and possibly other tumors that over-express SKP2. (Cancer Sci 2003; 94: 344–349)This publication has 20 references indexed in Scilit:
- A Novel Target Gene, SKP2, within the 5p13 Amplicon That Is Frequently Detected in Small Cell Lung CancersThe American Journal of Pathology, 2002
- S-Phase Kinase-Associated Protein 2 Expression in Non-Hodgkin's Lymphoma Inversely Correlates with p27 Expression and Defines Cells in S PhaseThe American Journal of Pathology, 2002
- Degradation of p27 at the G0-G1 Transition Mediated by a Skp2-independent Ubiquitination PathwayJournal of Biological Chemistry, 2001
- A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phaseNature, 2001
- Targeted disruption of Skp2 results in accumulation of cyclin E and p27Kip1, polyploidy and centrosome overduplicationThe EMBO Journal, 2000
- How the Cyclin Became a Cyclin: Regulated Proteolysis in the Cell CycleCell, 1999
- pl9skp1 and p45skp2 are essential elements of the cyclin A-CDK2 S phase kinaseCell, 1995
- Flow Cytometric Analyses of the Characteristics of Tumor Cells Treated with Two Platinum Compounds: 1,1‐Cyclobutanedicarboxylato(2‐aminomethylpyrrolidine)‐platinum(II) and CisplatinJapanese Journal of Cancer Research, 1992
- Secretion of antileucoprotease from a human lung tumor cell lineFEBS Letters, 1987
- Experimental parameters and a biological standard for acridine orange detection of drug-induced alterations in chromatin condensationCytometry, 1987