Down-regulation of SKP2 Induces Apoptosis in Lung-cancer Cells

Overview

Journal Cancer Sci

Specialty Oncology

Date 2003 Jun 26

PMID 12824902

Citations 24

Authors

Sana Yokoi

Kohichiroh Yasui

Toshihiko Iizasa

Takashi Takahashi

Takehiko Fujisawa

Johji Inazawa

Affiliations

Soon will be listed here.

Abstract

S-Phase kinase associated protein 2 (SKP2), an F-box protein constituting the substrate-recognition subunit of the SCF(SKP2) ubiquitin ligase complex, targets cell-cycle regulators, such as the cyclin-dependent kinase inhibitor p27(KIP1), 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 antisense 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 [(3)H]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.

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References

Latres E, Chiarle R, Schulman B, Pavletich N, Pellicer A, Inghirami G . Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci U S A. 2001; 98(5):2515-20. PMC: 30169. DOI: 10.1073/pnas.041475098. View

Malek N, Sundberg H, McGrew S, Nakayama K, Kyriakides T, Roberts J . A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature. 2001; 413(6853):323-7. DOI: 10.1038/35095083. View

Marti A, Wirbelauer C, Scheffner M, Krek W . Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation. Nat Cell Biol. 1999; 1(1):14-9. DOI: 10.1038/8984. View

Kudo Y, Kitajima S, Sato S, Miyauchi M, Ogawa I, Takata T . High expression of S-phase kinase-interacting protein 2, human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. Cancer Res. 2001; 61(19):7044-7. View

Appelhans B, Ender B, Sachse G, Nikiforov T, Appelhans H, Ebert W . Secretion of antileucoprotease from a human lung tumor cell line. FEBS Lett. 1987; 224(1):14-8. DOI: 10.1016/0014-5793(87)80413-1. View

Yokoi S, Yasui K, Saito-Ohara F, Koshikawa K, Iizasa T, Fujisawa T . A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol. 2002; 161(1):207-16. PMC: 1850681. DOI: 10.1016/S0002-9440(10)64172-7. View

Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U . p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol. 1999; 1(4):207-14. DOI: 10.1038/12027. View

Katayose Y, Kim M, Rakkar A, Li Z, Cowan K, Seth P . Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res. 1998; 57(24):5441-5. View

Nagahama H, Minamishima Y, Matsumoto M, Nakamichi I, Kitagawa K, Shirane M . Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J. 2000; 19(9):2069-81. PMC: 305685. DOI: 10.1093/emboj/19.9.2069. View

10.

Yu Z, Gervais J, Zhang H . Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci U S A. 1998; 95(19):11324-9. PMC: 21641. DOI: 10.1073/pnas.95.19.11324. View

11.

Block A, Bauer K, Williams T, Seidenfeld J . Experimental parameters and a biological standard for acridine orange detection of drug-induced alterations in chromatin condensation. Cytometry. 1987; 8(2):163-9. DOI: 10.1002/cyto.990080209. View

12.

Zhang H, Kobayashi R, Galaktionov K, Beach D . p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell. 1995; 82(6):915-25. DOI: 10.1016/0092-8674(95)90271-6. View

13.

Masuda T, Inoue H, Sonoda H, Mine S, Yoshikawa Y, Nakayama K . Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res. 2002; 62(13):3819-25. View

14.

Mendez J, Kim S, Hidaka M, Tansey W, Stillman B . Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol Cell. 2002; 9(3):481-91. DOI: 10.1016/s1097-2765(02)00467-7. View

15.

Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J . Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci U S A. 2001; 98(9):5043-8. PMC: 33160. DOI: 10.1073/pnas.081474898. View

16.

Hershko D, Bornstein G, Ben-Izhak O, Carrano A, Pagano M, Krausz M . Inverse relation between levels of p27(Kip1) and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas. Cancer. 2001; 91(9):1745-51. DOI: 10.1002/1097-0142(20010501)91:9<1745::aid-cncr1193>3.0.co;2-h. View

17.

Inoue S, Mizuno S, Ito M, Ohnuma T . Flow cytometric analyses of the characteristics of tumor cells treated with two platinum compounds: 1,1-cyclobutanedicarboxylato(2-aminomethylpyrrolidine)- platinum(II) and cisplatin. Jpn J Cancer Res. 1992; 83(11):1231-40. PMC: 5918718. DOI: 10.1111/j.1349-7006.1992.tb02750.x. View

18.

Obata Y, Sekido Y, Hida T, Ueda R, Watanabe H, Ariyoshi Y . Expression and amplification of myc gene family in small cell lung cancer and its relation to biological characteristics. Cancer Res. 1989; 49(10):2683-8. View

19.

Hara T, Kamura T, Oshikawa K, Hatakeyama S, Nakayama K . Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem. 2001; 276(52):48937-43. DOI: 10.1074/jbc.M107274200. View

20.

Slingerland J, Pagano M . Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol. 2000; 183(1):10-7. DOI: 10.1002/(SICI)1097-4652(200004)183:1<10::AID-JCP2>3.0.CO;2-I. View