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Published on: August 21, 2019
Siah1 proteins enhance radiosensitivity of human breast cancer cells
Hai-Tao He1, Emmanouil Fokas, An You
1Department of Radiotherapy and Radiation Oncology, Philipps-University Marburg, Baldingerstr, D-35043 Marburg, Germany.
Background:
Siah proteins play an important role in cancer progression. We evaluated the effect of Siah1, its splice variants Siah1L and the Siah1 mutant with the RING finger deleted (Siah1DeltaR) on radiosensitization of human breast cancer cells.
Methods:
The status of Siah1 and Siah1L was analysed in five breast cancer cell lines. To establish stable cells, SKBR3 cells were transfected with Siah1, Siah-1L and Siah1DeltaR. Siah1 function was suppressed by siRNA in MCF-7 cells. The impact of Siah1 overexpression and silencing on apoptosis, proliferation, survival, invasion ability and DNA repair was assessed in SKBR3 and MCF-7 cells, also in regards to radiation.
Results:
Siah1 and Siah1L mRNA expression was absent in four of five breast cancer cells lines analysed. Overexpression of Siah1 and Siah1L enhanced radiation-induced apoptosis in stable transfected SKBR3 cells, while Siah1DeltaR failed to show this effect. In addition, Siah1 and Siah1L significantly reduced cell clonogenic survival and proliferation. Siah1L sensitization enhancement ratio values were over 1.5 and 4.0 for clonogenic survival and proliferation, respectively, pointing to a highly cooperative and potentially synergistic fashion with radiation. Siah1 or Siah1L significantly reduced invasion ability of SKBR3 and suppressed Tcf/Lef factor activity. Importantly, Siah1 siRNA demonstrated opposite effects in MCF-7 cells. Siah1 and Siah1L overexpression resulted in inhibition of DNA repair as inferred by increased levels of DNA double-strand breaks in irradiated SKBR3 cells.
Conclusion:
Our results reveal for the first time how overexpression of Siah1L and Siah1 can determine radiosensitivity of breast cancer cells. These findings suggest that development of drugs augmenting Siah1 and Siah1L activity could be a novel approach in improving tumor cell kill.
Insights
Overexpression of Siah1 and Siah1L enhances breast cancer cell radiosensitivity by increasing apoptosis and inhibiting DNA repair. This suggests Siah1 and Siah1L augmenting drugs could improve tumor cell kill.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Siah proteins are implicated in cancer progression.
- The role of Siah1 and its splice variants in breast cancer radiosensitization requires further investigation.
Purpose of the Study:
- To evaluate the effect of Siah1, Siah1L, and Siah1DeltaR on the radiosensitization of human breast cancer cells.
- To assess the impact of Siah1 overexpression and silencing on cellular processes including apoptosis, proliferation, survival, invasion, and DNA repair in the context of radiation therapy.
Main Methods:
- Analysis of Siah1 and Siah1L mRNA expression in five breast cancer cell lines.
- Stable transfection of SKBR3 cells with Siah1, Siah-1L, and Siah1DeltaR.
- Siah1 function suppression using siRNA in MCF-7 cells.
- Assessment of apoptosis, proliferation, survival, invasion, and DNA repair in response to radiation following Siah1 manipulation.
Main Results:
- Siah1 and Siah1L mRNA were absent in most cell lines analyzed.
- Overexpression of Siah1 and Siah1L enhanced radiation-induced apoptosis and reduced clonogenic survival and proliferation in SKBR3 cells.
- Siah1 and Siah1L overexpression inhibited DNA repair, evidenced by increased DNA double-strand breaks.
- Siah1 siRNA showed opposite effects in MCF-7 cells, and Siah1/Siah1L reduced invasion ability and Tcf/Lef activity.
Conclusions:
- Siah1 and Siah1L overexpression significantly influence breast cancer cell radiosensitivity.
- Targeting Siah1 and Siah1L activity presents a potential therapeutic strategy for enhancing tumor cell kill in cancer treatment.
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