1. Department of Radiation Oncology, Chi-Mei Foundation Medical Center, Tainan, Taiwan.
2. School of Medicine, Taipei Medical University, Taipei, Taiwan.
3. Chung Hwa University of Medical Technology, Tainan, Taiwan.
4. Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei City, Taiwan.
5. School of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan.
6. Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung, Taiwan.
7. School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
8. Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
#These authors contributed equally to this work.
Radioresistant cells cause recurrence in patients with breast cancer after they undergo radiation therapy. The molecular mechanisms by which cancer cells obtain radioresistance should be understood to develop radiation-sensitizing agents. Results showed that the protein expression and activity of NAD(P)H:quinone oxidoreductase 1 (NQO1) were upregulated in radioresistant MDA-MB-231 triple-negative breast cancer (TNBC) cells. NQO1 knockdown inhibited the proliferation of NQO1 expressing Hs578t TNBC cells or the radioresistant MDA-MB-231 cells, whereas NOQ1 overexpression increased the survival of MDA-MB-231 cells, which lack of NQO1 expression originally, under irradiation. The cytotoxicity of β-lapachone, an NQO1-dependent bioactivatable compound, was greater in radioresistant MDA-MB-231 cells than in parental cells. β-lapachone displayed a radiosensitization effect on Hs578t or radioresistant MBDA-MB-231 cells. The expression of the long noncoding RNA NEAT1 positively regulated the NQO1 expression in radioresistant MDA-MB-231 cells at a translational level rather than at a transcription level. The inhibition of the NEAT1 expression through the CRISPR-Cas9 method increased the sensitivity of radioresistant MDA-MB-231 cells to radiation and decreased their proliferation, the activity of cancer stem cells, and the expression of stemness genes, including BMI1, Oct4, and Sox2. In conclusion, the NQO1 expression in triple-negative breast cancer cells determined their radiosensitivity and was controlled by NEAT1. In addition, NOQ1 bioactivatable compounds displayed potential for application in the development of radiation sensitizers in breast cancer.
Keywords: NAD(P)H:quinone oxidoreductase 1, radiosensitivity, triple negative breast cancer, long non-coding RNA NEAT1