Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ijms22115504
Keywords
bortezomib; P-glycoprotein; L1210 cells; cyclin-dependent kinases; cyclins; CDK inhibitors; ubiquitination; deubiquitinases; 26S proteasome; HSP90
Funding
- Slovak Agency for Research and Development [APVV-19-0093, APVV-19-0094]
- Ministry of Education of the Slovak Republic
- Slovak Academy of Sciences [VEGA 2/0157/18, VEGA 2/0070/19, VEGA 2/0159/19, VEGA 2/0171/21, APP0011]
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Bortezomib showed varying effects on different cell variants, but these effects were not sufficient to decrease cell sensitivity to bortezomib.
In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. We also observed an increase in the level of polyubiquitinated proteins (via K48-linkage) and a decrease in the gene expression of some deubiquitinases after treatment with bortezomib. Resistant cells expressed higher levels of genes encoding 26S proteasome components and the chaperone HSP90, which is involved in 26S proteasome assembly. After 4 h of preincubation, bortezomib induced a more pronounced depression of proteasome activity in S cells than in R or T cells. However, none of these changes alone or in combination sufficiently suppressed the sensitivity of R or T cells to bortezomib, which remained at a level similar to that of S cells.
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