| dc.description.abstract | Colorectal cancer is one of the common cancers around the world. The therapy strategy for colorectal cancer is mainly dependent on surgery combined with chemotherapy and radiotherapy, which is effective in the early stage of colorectal cancer but poorly effective in the metastasis stage. Hence, it’s in urgent need of discovery effective chemotherapy for colorectal cancer. Nuclear factor erythroid 2–related factor 2 (Nrf2) regulates oxidative homeostasis and metabolic process in cancer cells Evidence has shown that tumor cells highly depend on sustained activation of Nrf2 for survival and proliferation, also known as Nrf2 addiction, which is associated with cancer cell metastasis and poor prognosis. Therefore, targeting Nrf2 is a promising therapeutic strategy for Nrf2-addicted cancers. In this study, we determined the anticancer effects of L-Selenocystine (SeC) in Nrf2-addicted colorectal cancer cells We compared the levels of Nrf2 and Nrf2-regulated proteins in mesenchymal stem cell (MSC), colorectal cancers (WiDr and C2BBe1). WiDr cells had Nrf2-addiction characteristics, and MSCs are the non-Nrf2-addicted cancers. Compared with WiDr cells, C2BBe1 cells express moderate levels of Nrf2 and Nrf2 regulated proteins. We found that SeC induced the highest cytotoxicity and ROS production in WiDr cells. After SeC treatment, Nrf2/Keap1/p62 pathway was inhibited in WiDr cells but activated in MSCs. Moreover, SeC treatment increased cytosolic and mitochondrial superoxides production in WiDr cells but not in C2BBe1 cells. Antioxidants decreased SeC-induced oxidative stress, rescued cytotoxicity of SeC, and increased levels of Nrf2-downstream proteins. Meanwhile, SeC treatment also decreased levels of autophagy proteins in WiDr cells but increased those in MSCs. We utilized autophagy inhibitors to clarify the role of autophagy in SeC-induced cell death. Autophagy inhibitor increased cell mortality in SeC-treated WiDr cells. Antioxidants partially recovered the expression of autophagy-associated proteins in SeC-treated WiDr cells. C2BBe1 cells had lower levels of Nrf2 which show a slower cytotoxic effect and Nrf2/Keap1/P62 inhibition comparison with those of in WiDr cells after SeC treatment. We utilized siRNA transfection to knock down Keap1 to mimic Nrf2 addicted status, the sensitivity to SeC and ROS production were increased in SeC-treated C2BBe1 cells. However, Nrf2 knockdown recovers the cell viability after treatment in WiDr cells. In summary, our results indicated that SeC effectively inhibits Nrf2 and autophagy pathway, and triggers oxidative stress, leading to cell death in Nrf2-addicted cancer cells. | en_US |