Arsenic trioxide-mediated suppression of miR-182-5p is associated with potent anti-oxidant effects through up-regulation ofSESN2

Abstract

Arsenic trioxide (ATO) is a traditional Chinese medicine that can induce oxidative stress for treatment of cancer cells. However, ATO may generate anti-oxidative responses to compromise the cytotoxic effect, but the underlying mechanisms remain unclear. Here we found that ATO could inhibit miR-182-5p expression in patient-derived primary S1 glioblastoma (GBM) cells accompanied by up-regulation of Sestrin-2 (SESN2) mRNA, a known anti-oxidant molecule. This phenomenon was also detected in a U87MG glioma cell line, human lung adenocarcinoma H1299 cell line and A549 cell line. Pretreatment with a free radical scavenger N-acetylcysteine (NAC) reduced the oxidative stress induced by ATO. Concomitantly, ATO mediated suppression of miR-182-5p and enhancement of SESN2 expression were also compromised. The MTT assay further showed that ATO induced cytotoxicity was enhanced by transfection of miR-182-5p mimics. Overexpression of miR-182-5p mimics significantly suppressed the expression of SENS2 and a firefly luciferase reporter gene fused to 3’- untranslated region (UTR) of SESN2 mRNA. Use of ribonucleoprotein immunoprecipitation (RNP-IP), ATO mediated suppression of miR-182-5p led to the stabilization of SESN2 mRNA as a result of Argonaute-2 (AGO2) dependent gene silencing. Furthermore, high expression of miR-182-5p and low expression of SESN2 mRNA tend to be associated with longer survival of glioma or lung cancer patients using public available gene expression datasets and online tools for prediction of clinical outcomes. Taken together, current data suggest that the miR-182-5p/SENS2 pathway is involved in ATO induced anti-oxidant responses, which may be important for the design of novel strategy for cancer treatment.

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

“…Both UVB and UVA induce Sesn2 upregulation in melanocytes and melanoma cells suggesting the oncogenic role of Sesn2 in melanoma skin cancer (Zhao et al, 2017). The gene expression of Sesn2 upregulated by miR182-5p suppression in arsenic treatment functions as an antioxidant in Uppsala 87 malignant glioma (U87MG), human lung adenocarcinoma H1299, and A549 cell lines (Lin et al, 2018). Sesn2 would promote colorectal cancer cell growth in the iron-rich environment by suppressing ROS (Kim et al, 2019).…”

A paradoxical role for sestrin 2 protein in tumor suppression and tumorigenesis

“…Furthermore, these authors showed that overexpressed sestrin 2 was a marker for poor prognosis in lung cancer by analyzing the PrognoScan database and Kaplan–Meier Plotter [ 44 ]. Additionally, by analyzing data from the Gene Expression Omnibus and Cancer Genome Atlas analysis, Lin et al revealed that the survival time for lung cancer patients with lower sestrin 2 expression was significantly prolonged [ 45 ].…”

Sestrins as a Therapeutic Bridge between ROS and Autophagy in Cancer

“…Many purified compounds from dietary sources have been investigated for their anticancer activities through a direct modulation of SESN expression [80,81,82,83,84,85,86,87,88].…”

“…Puzzlingly, ATO can also promote antioxidant activities that can compromise its desired effects in a context-dependent manner [120]. Liang-Ting et al reported that ATO suppresses miR-182-5p expression in several cancer cell lines, correlating with the upregulation of SESN2 mRNA [85]. The pre-treatment with the free radical scavenger N-acetyl-cysteine (NAC) reduced oxidative stress and ATO-mediated suppression of miR-182-5p as well as the associated enhancement of SESN2 expression.…”

“…The pre-treatment with the free radical scavenger N-acetyl-cysteine (NAC) reduced oxidative stress and ATO-mediated suppression of miR-182-5p as well as the associated enhancement of SESN2 expression. Importantly, supply of miR-182-5p-mimicking molecules significantly suppressed the expression of SESN2 and was associated with longer survival of glioma or lung cancer patients [85]. This example underscores the importance of considering these types of relationships when designing therapeutic approaches in relation to the modulation of SESN2.…”