Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma

Lam, Sze‐Kwan; Mak, Judith C.W.; Zheng, Chunyan; Li, Yuanyuan; Kwong, Yok–Lam; Ho, J. C.

doi:10.3892/ijo.2014.2364

Cited by 20 publications

(18 citation statements)

References 38 publications

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“…Arsenic is known to enhance SUMOylation and degradation of PML-RARα (47), and has been shown to affect TYMS expression levels (48). In vitro SUMOylation of recombinant MTHFD1 protein was enhanced by As 2 O 3 pretreatment (Fig.…”

Section: Mthfd1mentioning

confidence: 97%

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Kamynina

Lachenauer

DiRisio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)-and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As 2 O 3 ), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery. As 2 O 3 exposure increased MTHFD1 SUMOylation in cultured cells and in in vitro SUMOylation reactions, and increased MTHFD1 ubiquitination and MTHFD1 and SHMT1 degradation. As 2 O 3 inhibited de novo dTMP biosynthesis in a dose-dependent manner, increased uracil levels in nuclear DNA, and increased genome instability. These results demonstrate that MTHFD1 and SHMT1, which are key enzymes providing one-carbon units for dTMP biosynthesis in the form of 5,10-methylenetetrahydrofolate, are direct targets of As 2 O 3 -induced proteolytic degradation, providing a mechanism for arsenic in the etiology of cancer and developmental anomalies.MTHFD1 | arsenic trioxide | one-carbon metabolism | SUMO-1

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Section: Mthfd1mentioning

confidence: 97%

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Kamynina

Lachenauer

DiRisio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…ATO induces growth inhibition and apoptosis in NSCLC cells through G2/M cell cycle arrest (13,14), Bcl-2 downregulation and GSH depletion (15). Recently, downregulation of thymidylate synthase and E2F1 were observed in lung adenocarcinoma (16,17) and mesothelioma (18). Synergistic effects have been observed when combining ATO with cisplatin (19), buthionine sulfoximine (BSO) (15), suberoylanilide hydroxamic acid (20), and sulindac (21).…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

Zheng

Lam

et al. 2015

Int J Oncol

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Abstract. Arsenic trioxide (ATO) has demonstrated anticancer activity in different malignancies, especially acute promyelocytic leukemia, with a wide array of putative mechanisms. In this study, we aimed to elucidate the activity and mechanisms of ATO in small cell lung cancer (SCLC). A panel of SCLC cell lines (H841, DMS79, H526, H69 and H187) was employed to demonstrate the activity of ATO. Cell viability, apoptosis and mitochondrial membrane depolarization were assessed. Western blotting was performed to determine the alteration of pro-apoptotic and anti-apoptotic mediators. Reactive oxygen species (ROS) (hydrogen peroxide and superoxide) and intracellular glutathione (GSH) were measured. Antioxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), were applied to restore GSH content and reduce production of ROS. All SCLC cell lines were relatively sensitive to ATO with IC 50 values below 10 µM. ATO induced cell death mainly through apoptosis in H841 cells in a dose-dependent manner. Hydrogen peroxide was the major ROS in SCLC cells induced by ATO. Along with GSH depletion and Bcl-2 downregulation, mitochondrial membrane permeabilization was enhanced, followed by release of AIF and SMAC from mitochondria to initiate different cell death pathways. NAC reversed cell death and molecular changes induced by ATO via restoring GSH and reducing ROS content. BHA inhibited hydrogen peroxide production completely and partially restored GSH content accounting for partial reversal of cell inhibition and mitochondrial dysfunction. Nonetheless, ATO reduced both reduced and oxidized form of thioredoxin 1 (Trx1) with no effect on Trx1 redox potential. ATO led to cell death in SCLC mainly through mitochondrial dysfunction, resulting from altered cellular redox homeostasis, namely, hydrogen peroxide generation, GSH depletion and Trx1 downregulation. IntroductionSCLC, accounting for 15-20% of newly diagnosed lung cancer, is an extremely aggressive malignancy with early metastasis and poor prognosis. Despite a prompt response to chemotherapy, relapses occur in the majority of patients with SCLC. Therefore the development of an alternative therapy against SCLC becomes imperative (1).ATO has been proven to be an effective therapeutic agent in acute promyelocytic leukemia (APL) with high complete remission rate and prolonged survival (2,3). ATO can induce apoptosis through PML-RARα-independent pathways in APL or other cancer cells via p53 activation (4,5), Bcl-2 downregulation (6,7), mitochondrial membrane depolarization and cytochrome c release (8-10), depletion of intracellular reduced glutathione (GSH) content and elevation of reactive oxygen species (11,12). More recently, the application of ATO in lung cancer treatment has been explored in preclinical models, mainly in non-small cell lung cancer (NSCLC). ATO induces growth inhibition and apoptosis in NSCLC cells through G2/M cell cycle arrest (13,14), Bcl-2 downregulation and GSH depletion (15). Recently, downregulation of thymidylate synthase and E2F1 were obser...

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“…This enzyme is a downstream target of the transcription factor E2F1. 22 DEN administration induced Tyms mRNA and E2F1 protein levels. Notably, in the 18-D + IFC group, both were down-regulated, and in the 12-18-D + IFC, decreased Tyms expression was observed.…”

Section: Discussionmentioning

confidence: 99%

Cancer chemoprevention by an adenosine derivative in a model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats

et al. 2017

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Hepatocellular carcinoma is one of the most common cancers, and approximately 80% develop from cirrhotic livers. We have previously shown that the aspartate salt of adenosine prevents and reverses carbon tetrachloride-induced liver fibrosis in rats. Considering the hepatoprotective role of this adenosine derivative in fibrogenesis, we were interested in evaluating its effect in a hepatocarcinogenesis model induced by diethylnitrosamine in rats, where multinodular cancer is preceded by cirrhosis. Rats were injected with diethylnitrosamine for 12 weeks to induce cirrhosis and for 16 weeks to induce hepatocarcinogenesis. Groups of rats were treated with aspartate salt of adenosine from the beginning of carcinogen administration for 12 or 18 weeks total, and another group received the compound from weeks 12 to 18. Fibrogenesis was estimated and the proportion of preneoplastic nodules and tumors was measured. The apoptotic and proliferation rates in liver tissues were evaluated, as well as the expression of cell signaling and cell cycle proteins participating in hepatocarcinogenesis. The adenosine derivative treatment reduced diethylnitrosamine-induced collagen expression and decreased the proportion of nodules positive for the tumor marker γ-glutamyl transferase. This compound down-regulated the expression of thymidylate synthase and hepatocyte growth factor, and augmented the protein level of the cell cycle inhibitor p27; these effects could be part of its chemopreventive mechanism. These findings suggest a hepatoprotective role of aspartate salt of adenosine that could be used as a therapeutic compound in the prevention of liver tumorigenesis as described earlier for hepatic fibrosis.

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Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma

Cited by 20 publications

References 38 publications

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

Cancer chemoprevention by an adenosine derivative in a model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats

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