Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells.
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.
Desai
S D
SD
Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA.
Li
T K
TK
Rodriguez-Bauman
A
A
Rubin
E H
EH
Liu
L F
LF
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D016466:CHO Cells; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D006224:Cricetinae; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014452:Ubiquitins / Q000378:metabolism*
D014452:Ubiquitins; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin