miR-155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells

Abstract

Arsenic trioxide (ATO) resistance is a challenging problem in chemotherapy. However, the underlying mechanisms remain to be elucidated. In this study, we identified a high level of expression of miR-155 in a human lung adenocarcinoma A549R cell line that is highly resistant to ATO. We showed that the high level of miR-155 was associated with increased levels of cell survival, colony formation, cell migration and decreased cellular apoptosis, and this was mediated by high levels of Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and a high ratio of Bcl-2/Bax. Overexpression of the miR-155 mimic in A549R cells resulted in increased levels of colony formation and cell migration as well as reduced apoptosis along with increased Nrf2, NQO1 and HO-1. In contrast, silencing of miR-155 expression with its inhibitor in the cells, significantly decreased the cellular levels of Nrf2, NQO1 and HO-1 as well as the ratio of Bcl-2/Bax. This subsequently reduced the level of colony formation and cell migration facilitating ATO-induced apoptosis. Our results indicate that miR-155 mediated ATO resistance by upregulating the Nrf2 signaling pathway, but downregulating cellular apoptosis in lung cancer cells. Our study provides new insights into miR-155-mediated ATO resistance in lung cancer cells.

MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress

“…As mentioned earlier; one of the difficulties faced in chemotherapy is the development of resistance to chemotherapeutic agents (Li et al, 2008). It appears that miR-155 is involved in the resistance of tumor cells into ATO (Gu et al , 2017). It has been shown that miR-155 makes lung cancer cells resistant to ATO by the activation of the Nrf2 signaling pathway.…”

Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

“…The interaction between tRNAs and ferroptosis includes two possible manners. First, tRNAs are required in the synthesis of ferroptosis associated factors such as SLC7A11, GPX4, and IREB2, thus the mutation of tRNAs may alter the expression of these factors and then influence ferroptosis 217 . Second, tRNAs have multiple interaction partners including aminoacyl-tRNA-synthetases, mRNAs, ribosomes and translation factors 159 .…”

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

“…More recently, the involvement of miRNAs in regulating HO-1 in cancer cells has been proved. In particular, miR-155 favors lung cancer resistance to arsenic trioxide through Nrf2/HO-1 activation [ 78 ]. miR200a, in breast cancer, regulates HO-1 via Nrf2 activation by targeting Keap1 mRNA [ 79 ].…”