The involvement of NAD(P)H-Quinone Oxidoreductase 1 in radiation response of human breast cancer cells

• Main Authors: Mu-Ya Chang, 張慕亞
• Other Authors: Wen-Wei Chang
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/3h3x3b

碩士 === 中山醫學大學 === 生物醫學科學學系碩士班 === 106 === Breast cancer is one of the common cancer in women worldwide. In recent years, the radiation therapy was used as a common therapy in breast cancer and often combined with other treatments. The NAD(P)H-Quinone Oxidoreductase 1 (NQO1) is an FAD containing quinone reductase that catalyzes the 2-electron reduction of a broad range of quinones to provide cytoprotection and chemoprevention in normal tissue. NQO1 also presents high-level activity in many inflammatory conditions and in the tumorous tissues, such as breast, lung, and gastric cancers. In the present study, our laboratory used the MDA-MB-231 human breast cancer cell line (called 231-P) to establish a radioresistant subline (called 231-RR) and to examine the NQO1 expression in breast cancer cells after requiring radioresistant feature. We first confirmed that the NQO1 protein expression was elevated in 231-RR then that in 231-P cells to 40 fold. In addition, the NQO1 activity was also increased in 231-RR cells then 231-P cells. We further used beta-Lapachone, which is bioactivated by NQO1 to become cytotoxic, to compare the sensitivity between 231-P and 231-RR cells and results indicated that 231-RR was more sensitive to growth inhibition by beta-Lapachone then 231-P cells. With the treatment of dicoumarol, an NQO1 inhibitor, the inhibition of NQO1 activity suppressed cell growth of 231-RR cells. We using dicoumarol or beta-Lapachone to treated cells followed by radiation exposure and found that the radiosensitivity of 231-RR were obviously elevated by pre-treatment these two compounds. These results indicated that NQO1 inhibitors or NQO1 bioactive compounds could serve as an adjuvant therapy for cancer radiation therapy. When investigated the underlying molecular pathway of NQO1 upregulation in radioresisant breast cancer cells, we found that inhibition of Notch or JNK activity by specific inhibitors did not influence the expression of NQO1 protein. Taken together, our results indicate that NQO1 is a potential target for treatment of breast cancer patients who encounter with radiation therapy failure. In the future, it is necessary to examine the underlying molecular mechanism in the upregulation of NQO1 in radioresistant breast cancer cells.