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Diaphanous-related formin 1 as a target for tumor therapy
Yuan-Na Lin1,2, Sabine Windhorst2
1Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
Abstract:
Formins nucleate actin and stabilize microtubules (MTs). Expression of the formin Diaphanous homolog 1 (DIAPH1) is increased in malignant colon carcinoma cells, while expression of DIAPH3 is up-regulated in breast and prostate carcinoma cells. Both DIAPH1 isoforms are required to stabilize interphase MTs of cancer cells, and it has been shown that loss of this function decreases the metastatic potential of these cells. Moreover, depletion of DIAPH3 increases the sensitivity of breast and prostate carcinoma cells to taxanes. In contrast with DIAPH1 + 3, DIAPH2 regulates metaphase MTs of tumor cells by stabilizing binding of kinetochore MTs to chromosomes. Depletion of DIAPH2 impairs chromosome alignment, thus proper chromosome segregation during mitosis. In summary, expression of DIAPH formins in tumor cells is essential for stabilizing interphase or metaphase MTs, respectively. Thus, it would be very interesting to analyze if tumor cells exhibiting low DIAPH expression are more sensitive to taxanes than those with high DIAPH expression.
Insights
Formins are proteins that stabilize microtubules (MTs) in cancer cells. Lowering DIAPH formin expression may increase cancer cell sensitivity to taxane drugs, suggesting a new therapeutic strategy.
Area of Science:
- Cell Biology
- Cancer Research
- Microtubule Dynamics
Background:
- Formins are proteins that nucleate actin filaments and stabilize microtubules (MTs).
- Specific formins, DIAPH1 and DIAPH3, are upregulated in colon, breast, and prostate carcinomas and stabilize interphase MTs.
- DIAPH2 regulates metaphase MTs by stabilizing kinetochore-chromosome interactions, crucial for proper mitosis.
Purpose of the Study:
- To investigate the role of DIAPH formins in cancer cell biology.
- To explore the potential of targeting DIAPH formins for cancer therapy, particularly in relation to taxane sensitivity.
Main Methods:
- Analysis of DIAPH1, DIAPH2, and DIAPH3 expression in various carcinoma cells.
- Investigating the function of DIAPH formins in stabilizing interphase and metaphase microtubules.
- Assessing the impact of DIAPH formin depletion on cancer cell metastasis and sensitivity to taxanes.
Main Results:
- DIAPH1 and DIAPH3 stabilize interphase MTs in cancer cells; their depletion reduces metastatic potential.
- DIAPH3 depletion enhances the sensitivity of breast and prostate cancer cells to taxanes.
- DIAPH2 stabilizes MTs at kinetochores, and its depletion impairs chromosome segregation during mitosis.
Conclusions:
- DIAPH formins play critical roles in stabilizing MTs in both interphase and mitosis within tumor cells.
- Tumor cells with low DIAPH expression may exhibit increased sensitivity to taxane-based chemotherapy.
- Targeting DIAPH formins could represent a novel therapeutic strategy to overcome taxane resistance in cancer.
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