Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1.

Autor: Zhang VX; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Sze KM; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Chan LK; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Ho DW; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Tsui YM; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Chiu YT; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Lee E; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Husain A; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Huang H; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Tian L; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Wong CC; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR., Ng IO; Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong SAR. iolng@hku.hk.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR. iolng@hku.hk.
Jazyk: angličtina
Zdroj: Cell & bioscience [Cell Biosci] 2021 Dec 19; Vol. 11 (1), pp. 217. Date of Electronic Publication: 2021 Dec 19.
DOI: 10.1186/s13578-021-00731-0
Abstrakt: Background: Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth.
Methods: Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets.
Results: In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo.
Conclusions: Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.
(© 2021. The Author(s).)
Databáze: MEDLINE
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