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Weakened spindle checkpoint with reduced BubR1 expression in paclitaxel-resistant ovarian carcinoma cell line
Yunfeng Fu1, Dafeng Ye, Huaizeng Chen
1Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
Objective:
Paclitaxel sensitivity has recently been associated with the spindle checkpoint. The aim of our study is to investigate the status of spindle checkpoint and the alteration of its major components in phenotype with acquired paclitaxel resistance in ovarian carcinoma.
Methods:
A paclitaxel-resistant ovarian carcinoma cell line, SKOV3-TR30, with the resistant ability of 27-fold greater than its parental cell line, was derived from SKOV3 cell line. The competence of spindle checkpoint and the expression of the major spindle checkpoint proteins (BubR1 and Mad2) in SKOV3-TR30 cells were investigated.
Results:
Mitotic index and flow cytometric analysis revealed that SKOV3-TR30 cells were not arrested in M phase in contrast to SKOV3, which showed a clear mitotic arrest in the presence of paclitaxel or nocodazole. The expressions of securin and cyclin B in SKOV3-TR30 cells were significantly lower than those in SKOV3 cells, indicating the premature degradation of APC substrates in SKOV3-TR30 cells in response to spindle damagers. Chromosome spread analysis showed increased rate of premature sister chromatid segregation in SKOV3-TR30 cells. The expression of spindle checkpoint protein BubR1 was evidently lower in SKOV3-TR30 cells than that in SKOV3 cells. However, there was no significant difference in Mad2 expression between SKOV3-TR30 and SKOV3 cells.
Conclusions:
This study demonstrates that weakened spindle checkpoint with reduced expression of BubR1, but not Mad2, is associated with acquired paclitaxel resistance in ovarian carcinoma cells.
Insights
Acquired paclitaxel resistance in ovarian cancer is linked to a weakened spindle checkpoint. This involves reduced expression of BubR1, a key protein, but not Mad2, impacting cell division control.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Paclitaxel is a key chemotherapy agent for ovarian carcinoma.
- Drug resistance remains a significant challenge in ovarian cancer treatment.
- The spindle checkpoint plays a crucial role in maintaining genomic stability during cell division.
Purpose of the Study:
- To investigate the spindle checkpoint status in paclitaxel-resistant ovarian cancer cells.
- To identify alterations in major spindle checkpoint components associated with acquired resistance.
Main Methods:
- Developed a paclitaxel-resistant ovarian cancer cell line (SKOV3-TR30).
- Assessed mitotic arrest, protein expression (BubR1, Mad2, securin, cyclin B), and sister chromatid segregation.
Main Results:
- SKOV3-TR30 cells showed no mitotic arrest in response to paclitaxel, unlike parental cells.
- Premature degradation of APC substrates and increased sister chromatid segregation were observed.
- BubR1 expression was significantly reduced in resistant cells, while Mad2 expression remained unchanged.
Conclusions:
- Weakened spindle checkpoint function contributes to acquired paclitaxel resistance in ovarian carcinoma.
- Reduced BubR1 expression is specifically associated with this resistance phenotype.
- Mad2 expression levels do not appear to be a factor in this resistance mechanism.
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