Ubiquitin/26s proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells

S. D. Desai, T. K. Li, A. Rodriguez-Bauman, Leroy-Fong Liu, L. F. Liu

Research output: Contribution to journalArticle

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Abstract

Camptothecin (CPT) induces down-regulation of topoisomerase I (TOP1) via an ubiquitin/26S proteasome pathway. Studies using a panel of breast and colorectal cancer cell lines as well as primary nontransformed and oncogene-transformed cells have demonstrated that CPT-induced down-regulation exhibits a high degree of heterogeneity. In general, nontransformed cells are much more proficient in CPT-induced TOP1 down-regulation than their transformed counterparts. Among the breast and colorectal cancer cell lines, there was a general correlation between the extent of CPT-induced TOP1 down-regulation and CPT resistance. The breast cancer cell line ZR-75-1, the most sensitive to CPT, was completely defective in CPT-induced TOP1 down-regulation, whereas the breast cancer cell line BT474, the least sensitive to CPT, exhibited effective CPT-induced TOP1 down-regulation. The 26S proteasome inhibitor MG132 was shown to inhibit CPT-induced down-regulation of TOP1 in BT474 cells and selectively sensitized BT474 but not ZR-75-1 cells to CPT-induced cytotoxicity and apoptosis. In the aggregate, these results suggest that CPT-induced down-regulation of TOP1 could be an important parameter for determining CPT sensitivity/resistance in tumor cells. Analysis of the levels of TOP1 cleavable complexes, SUMO-1-TOP1 conjugates, and ubiquitin-TOP1 conjugates in ZR-75-1 and BT474 cells has suggested that the heterogeneity of CPT-induced down-regulation of TOP1 in tumor cells is at least in part attributable to altered regulation of a process(es) downstream from the TOP1 cleavable complex.

Original languageEnglish
Pages (from-to)5926-5932
Number of pages7
JournalCancer Research
Volume61
Issue number15
Publication statusPublished - Aug 1 2001
Externally publishedYes

Fingerprint

Camptothecin
Type I DNA Topoisomerase
Ubiquitin
Down-Regulation
Neoplasms
Breast Neoplasms
Cell Line
ATP dependent 26S protease
Colorectal Neoplasms
Proteasome Inhibitors
Oncogenes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ubiquitin/26s proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. / Desai, S. D.; Li, T. K.; Rodriguez-Bauman, A.; Liu, Leroy-Fong; Liu, L. F.

In: Cancer Research, Vol. 61, No. 15, 01.08.2001, p. 5926-5932.

Research output: Contribution to journalArticle

Desai, S. D. ; Li, T. K. ; Rodriguez-Bauman, A. ; Liu, Leroy-Fong ; Liu, L. F. / Ubiquitin/26s proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. In: Cancer Research. 2001 ; Vol. 61, No. 15. pp. 5926-5932.
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