Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

Lee, Derek; Xu, Mingjing; Chiu, David Kung‐Chun; Lai, Robin Kit-Ho; Tse, Aki Pui‐Wah; Li, Lynna Lan; Law, Cheuk‐Ting; Tsang, Felice Ho‐Ching; Wei, Larry Lai; Chan, Cerise Yuen‐Ki; Wong, Chun–Ming; Ng, Irene Oi–Lin; Wong, Carmen Chak‐Lui

doi:10.1172/jci90253

Cited by 103 publications

(111 citation statements)

References 56 publications

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“…Our group previously identified two growth‐promoting metabolic pathways, the folate cycle and PPP, as major producers of NADPH in human HCC (Fig. ) . Results from our current study targeting the NADPH‐dependent and NADPH‐using thioredoxin system echo our previous studies regarding the importance of intrinsic antioxidant‐producing pathways for cancer cell survival (Fig.…”

Section: Discussionsupporting

confidence: 84%

“…The thioredoxin system is driven by NADPH, which donates an electron to activate TXN for active ROS scavenging. Inhibitors targeting NADPH‐producing pathways such as methotrexate and oxythymine against the folate cycle and PPP, respectively, effectively inhibited NADPH production, which led to ROS accumulation and ultimately inhibited HCC growth . This study shows that blockade of the TXN system which receives NADPH after its production could also effectively suppress HCC growth.…”

Section: Discussionmentioning

confidence: 77%

“…It is composed of thioredoxin (TXN), thioredoxin reductase (TXNRD), and nicotinamide adenine dinucleotide phosphate, reduced form (NADPH). The thioredoxin system begins with electron donation from NADPH, which is generated from the pentose phosphate pathway (PPP), malate enzymes, or the folate cycle . TXNRD transfers the electron to TXN, which then transfers the electron for ROS scavenging.…”

mentioning

confidence: 99%

“…The thioredoxin system is activated in cancer, and TXNRD1 is overexpressed in a variety of solid cancers such as HCC, colorectal cancer, and prostate cancer . We recently identified the folate cycle as a major producer of NADPH to counteract oxidative stress in human HCC, and specific inhibition of a key folate cycle enzyme, methylenetetrahydrofolate dehydrogenase 1‐like, or a folate analogue, methotrexate, sensitizes HCC toward sorafenib treatment in vitro and in vivo . TXNRD1 has been suggested as a prognostic marker for human HCC patients .…”

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confidence: 99%

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Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant‐producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction‐oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid‐derived 2)–like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacological TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma

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“…In particular the combination strategies of Cygb with conventional chemoradiotherapies to overcome cancer therapy resistance or tumor relapse have been developed. The interaction of ONS with CSCs is a crucial driver throughout tumorigenesis and progression . We found that reduced GSH can attenuate the inhibition of Cygb on the growth of HCC spheres and LCSC phenotypes (Figures A, B, and E), it also blocks the promotion of Cygb knockdown to LCSC growth and phenotypes (Figure C–E).…”

Section: Discussionmentioning

confidence: 69%

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

Zhang

Pei

Yang

et al. 2018

Molecular Carcinogenesis

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Cancer stem cells (CSCs) account for tumor self‐renewal and heterogeneity. Oxidative‐nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS‐dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.

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Biochemical recurrence related metabolic novel signature associates with immunity and ADT treatment responses in prostate cancer

Wang

Xia

et al. 2022

Cancer Medicine

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Background Prostate cancer (PCa) is a unique cancer from a metabolic perspective. Androgen receptor assumes a vital part in normal and malignant prostate cells regarding almost all aspects of cell metabolism, such as glucose, fat, amino acids, nucleotides, and so on. Methods We used The Cancer Genome Atlas database as training set, Memorial Sloan‐Kettering Cancer Center cohort as validation set, and Gene Expression Omnibus database (GSE70769) as test set to identify the optimal prognostic signature. We evaluated the signature in terms of biochemical progression‐free survival (bPFS), ROC curve, clinicopathological features, independent prognostic indicators, tumor microenvironment, and infiltrating immune cells. Nomogram was built dependent on the results of cox regression analyses. GSEA algorithm was used to evaluate differences in metabolism. The signature's prediction of androgen deprivation therapy (ADT) response was validated based on two groups of basic cytological experiments treat with ADT (GSE143408 and GSE120343) and the transcriptional information of pre‐ADT/post‐ADT of six local PCa patients. Results We finally input four screened genes into the stepwise regression model to construct metabolism‐related signature. The signature shows good prediction performance in training set, verification set, and test set. A nomogram based on the PSA, Gleason score, T staging, and the signature risk score could predict 1‐, 3‐, and 5‐year bPFS with the high area under curve values. Based on gene‐set enrichment analysis, the characteristics of four genes signature could influence some important metabolic biological processes of PCa and were serendipitously found to be significantly related to androgen response. Subsequently, two cytological experimental data sets and our local patient sequencing data set verified that the signature may be helpful to evaluate the therapeutic response of PCa to ADT. Conclusions Our systematic study definite a metabolism‐related gene signature to foresee prognosis of PCa patients which might add to individual prevention and treatment.

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Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

Cited by 103 publications

References 56 publications

Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma

Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

Biochemical recurrence related metabolic novel signature associates with immunity and ADT treatment responses in prostate cancer

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