Notch signaling pathway mediates Doxorubicin-driven apoptosis in cancers

Abstract

Background: Doxorubicin is a widely used chemotherapy drug for the treatment of a variety of cancers, however it also has serious side effects such as anaphylaxis and heart damage. Therefore, it’s very important to understand the downstream molecular pathways that are essential for Doxorubicin function in cancer treatment. Methods: HeLa S3 cells were treated with different concentrations of Doxorubicin for 24 hours. Then, the mRNA levels of Notch pathway components in the Doxorubicin treated cells were determined by Real-Time qRT-PCR. Lentiviral transfection was used to up-regulate and downregulate HES1 expression. Cell proliferation and apoptosis were measured with MTT assay and flow cytometry. Finally, immunofluorescence was used to detect protein subcellular location. Result: Doxorubicin treatment strongly increases the expression of multiple Notch pathway components in cancer cells. The Notch target HES1 is activated by Doxorubicin and is required for the Doxorubicin driven apoptosis. In addition, over-expression of HES1 can further enhances Doxorubicin’s role in promoting apoptosis. Mechanistically, HES1 activates PARP1 and regulates the subcellular location of AIF to mediate the apoptosis response under Doxorubicin treatment. Conclusion: Our results provided novel insights into the downstream molecular pathways underlying Doxorubicin treatment and suggested that manipulation of Notch signaling pathway could have synergistic effect with Doxorubicin for cancer treatment.