NAD(P)H:quinone oxidoreductase 1 determines radiosensitivity of triple negative breast cancer cells and is controlled by long non-coding RNA NEAT1

Abstract

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.

Properties and gene expression profiling of acquired radioresistance in mouse breast cancer cells

“…However, it was interesting to note that the radioresistant phenotype in NF639R cells was still maintained after 30 passages. In fact, some researchers observed that 40 Gy irradiation is enough to induce radioresistance in some breast cancer cells such as MCF7 and MDA-MB-231 (43,44). However, radioresistant cells established by 40 Gy or less total dose radiation may be instable due to transient genetic changes.…”

Long and short non-coding RNA and radiation response: a review

“…51 Recently, Lin et al described the role of NEAT1 in regulating radioresistance by targeting NAD(P)H:quinone oxidoreductase 1 (NQO1). 52 They showed the positive regulation of NQO1 by NEAT1 at the translational level in radioresistant triple negative breast cancer cells. By inhibiting NEAT1, they were able to trigger oxidative stress and increase the radiosensitivity of the cells, 52 giving a potential treatment strategy for resistant cancer phenotypes.…”

lncRNA and breast cancer: Progress from identifying mechanisms to challenges and opportunities of clinical treatment

“…Inhibition of NEAT1 expression by CRISPR-Cas9 increases the sensitivity of radiation-resistant cells to radiation and reduces cell proliferation and the expression of tumor stem cell markers including BMI1, OCT4, and SOX2. 271 In addition, MEG3 knockout mediated by the CRISPR-Cas9 system significantly reduces the invasion ability of human triple-negative metastatic Hs578T cancer cells. 215 These evidences suggest that CRISPR-Cas9 genome editing can be used to precisely eliminate abnormally expressed lncRNAs in cancer cells, thereby providing a useful strategy to target oncogenes for the development of novel precision medicine therapies.…”