Abstract
Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants and found to have potential anticancer activities. However, the intracellular molecular targets of SLs and the underlying molecular mechanisms have not been well elucidated. In this study, we observed that EM23, a natural SL, exhibited anti-cancer activity in human cervical cancer cell lines by inducing apoptosis as indicated by caspase 3 activation, XIAP downregulation and mitochondrial dysfunction. Mechanistic studies indicated that EM23-induced apoptosis was mediated by reactive oxygen species (ROS) and the knockdown of thioredoxin (Trx) or thioredoxin reductase (TrxR) resulted in a reduction in apoptosis. EM23 attenuated TrxR activity by alkylation of C-terminal redox-active site Sec498 of TrxR and inhibited the expression levels of Trx/TrxR to facilitate ROS accumulation. Furthermore, inhibition of Trx/TrxR system resulted in the dissociation of ASK1 from Trx and the downstream activation of JNK. Pretreatment with ASK1/JNK inhibitors partially rescued cells from EM23-induced apoptosis. Additionally, EM23 inhibited Akt/mTOR pathway and induced autophagy, which was observed to be proapoptotic and mediated by ROS. Together, these results reveal a potential molecular mechanism for the apoptotic induction observed with SL compound EM23, and emphasize its putative role as a therapeutic agent for human cervical cancer.
Highlights
Thioredoxin reductase (TrxR) is a ubiquitously expressed oxidoreductase crucial for maintaining cellular redox homeostasis by counteracting the effects of reactive oxygen species (ROS) and regulating redoxrelated signaling cascades [1]
TrxR is the only enzyme known to catalyze the reduction of thioredoxin (Trx), which participates in wide variety of cellular processes including the oxidative stress response, gene regulation via the NF-κB, p53, and Ref-1 transcription factors, and the competitive inhibition of apoptosis-regulating signal kinase 1 (ASK1)-induced apoptosis [2]
To determine the effect of EM23 on the cellular growth inhibition, several human cancer cell lines were treated with varying concentrations of EM23 for 24 h, including lung cancer cell line A549; human breast cancer cell line MCF-7; human esophageal cancer cell lines TE-1, EC109, and EC9706; human cervical cancer cell lines CaSki and SiHa; and human leukemia cell lines HL-60 and K562
Summary
Thioredoxin reductase (TrxR) is a ubiquitously expressed oxidoreductase crucial for maintaining cellular redox homeostasis by counteracting the effects of reactive oxygen species (ROS) and regulating redoxrelated signaling cascades [1]. The Trx/TrxR system contributes to tumor cell resistance to oxidative stress-induced apoptosis [6], which is an important mechanism of various anticancer agents. Knock down of TrxR expression nearly abolished the capacity of lung cancer cells to form tumors in a xenograft model system [7]; over expression of the alternative splicing variant of TrxR induced apoptosis in HeLa cells [8]. Overall, these studies substantiate the notion that mammalian TrxR may be a promising drug target for cancer therapy
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