Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths globally. Despite advances in diagnosis and treatment, the incidence and mortality of HCC continue to rise. Piperlongumine (PL), an alkaloid isolated from the fruit of the long pepper, is known to selectively kill tumor tissues while sparing their normal counterparts. However, the killing effects of PL on HCC and the underlying mechanism of PL are not clear. We report that PL may interact with thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, and induce reactive oxygen species (ROS)-mediated apoptosis in HCC cells. Our results suggest that PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells by targeting TrxR1 and increasing intracellular ROS levels. Notably, PL treatment reduces TrxR1 activity and tumor cell burden in vivo. Additionally, TrxR1 is significantly upregulated in existing HCC databases and available HCC clinical specimens. Taken together, these results suggest PL as a novel anticancer candidate for the treatment of HCC. More importantly, this study reveals that TrxR1 might be an effective target in treating HCC.
Highlights
Liver cancer, the sixth most common human malignancy and the third leading cause of cancer mortality, is a major public health problem, and hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers (Zhou et al, 2017)
We evaluated whether the killing effect of PL on Hepatocellular carcinoma (HCC) cells was related to reactive oxygen species (ROS) accumulation
We detected the fluorescence intensity by a fluorescence microscope discovered that PL may increase the levels of intracellular ROS and that this effect was almost completely reversed by pretreatment of the cells with NAC (Figure 1E)
Summary
The sixth most common human malignancy and the third leading cause of cancer mortality, is a major public health problem, and hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers (Zhou et al, 2017). The effects of traditional systemic chemotherapy on HCC and the Abbreviations: ATF4, activating transcription factor 4; Bax, associated protein x; Bcl-2, Bcell lymphoma 2; Cdc, cyclindependent kinase 1 (cell division cycle protein 2); DCFH-DA, 2′, 7′-dichlorodihydrofluorescin diacetate; eIF2, eukaryotic initiation factor 2; ER, endoplasmic reticulum; HRP, horseradish peroxidase; Ki-67, nuclear protein associated with cell proliferation; MDA, malondialdehyde; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide; NAC, N-acetyl cysteine; PI, propidium iodide; ROS, reactive oxygen species. Recent studies demonstrated that PL is highly and selectively toxic toward cancer cells, strongly suggesting that PL is a promising bioactive agent for liver cancer therapy (Gong et al, 2014). PL has been proposed to induce cancer-selective cell death by elevating reactive oxygen species (ROS) levels (Jin et al, 2014). The mechanism by which PL induces ROS remains poorly defined, and the primary cellular target and mode of action of PL in HCC are still unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
