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Notch signaling pathway mediates Doxorubicin-driven apoptosis in cancers

Authors Huang Z, Lin S, Long C, Zhou X, Fan Y, Kuang X, He J, Ning J, Zhang H, Zhang Q, Shen H

Received 19 December 2017

Accepted for publication 8 March 2018

Published 8 June 2018 Volume 2018:10 Pages 1439—1448

DOI https://doi.org/10.2147/CMAR.S160315

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Harikrishna Nakshatri


Zixin Huang,1,* Shuibin Lin,2,* Chongde Long,1 Xin Zhou,1 Yuting Fan,1 Xielan Kuang,1,3 Jia He,1 Jie Ning,1 Han Zhang,1 Qingjiong Zhang,1 Huangxuan Shen1,3

1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; 2Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 3Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

*These authors contributed equally to this work

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 down-regulate 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.

Keywords: Doxorubicin, Notch, HES1, PARP1, apoptosis, cancer treatment

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