Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

Harris, Isaac S.; Treloar, Aislinn E.; Inoue, Satoshi; Sato, Masato; Gorrini, Chiara; Lee, Kim Chung; Yung, Ka Yi; Brenner, Dirk; Knobbe-Thomsen, Christiane B.; Cox, Maureen A.; Elia, Andrew; Berger, Thorsten; Cescon, David W.; Adeoye, Adewunmi; Brüstle, Anne; Molyneux, Sam D.; Mason, Jacqueline M.; Li, Wanda Y.; Yamamoto, Kazuo; Wakeham, Andrew; Berman, Hal K.; Khokha, Rama; Done, Susan J.; Kavanagh, Terrance J.; Lam, Charlene; Mak, Tak W.

doi:10.1016/j.ccell.2014.11.019

Cited by 799 publications

(565 citation statements)

References 41 publications

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“…Our data provide a mechanistic basis for the prooncogenic functions of C/EBP␥, especially its ability to control antioxidant pathways crucial for the progression and metastasis of advanced cancers (6). For example, the C/EBP␥ target gene Slc7a11 (xCT) encodes a component of the cystine transporter complex that provides a source of cysteine for synthesis of glutathione and thioredoxin, two key antioxidants in tumor cells (8). The importance of Slc7a11 in cancer is underscored by the observation that its expression is silenced by p53, and Slc7a11 downregulation contributes to tumor suppression independently of p53's ability to elicit apoptosis and senescence (68).…”

Section: Atf4mentioning

confidence: 99%

“…Elevated levels of reactive oxygen species (ROS) can initiate oncogenesis by causing DNA mutations and genome instability (6). However, recent studies have shown that, once established, tumor cells are reliant on antioxidant pathways for growth and survival (7,8). Moreover, radio-and chemotherapies induce death or senescence of cancer cells partly by increasing ROS.…”

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confidence: 99%

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C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4

Huggins

Mayekar

Martín

et al. 2016

Molecular and Cellular Biology

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eThe integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances, and endoplasmic reticulum (ER) stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here, we show that C/EBP␥:ATF4 heterodimers, but not C/EBP␤:ATF4 dimers, are the predominant CARE-binding species in stressed cells. C/EBP␥ and ATF4 associate with genomic CAREs in a mutually dependent manner and coregulate many ISR genes. In contrast, the C/EBP family members C/EBP␤ and C/EBP homologous protein (CHOP) were largely dispensable for induction of stress genes. Cebpg ؊/؊ mouse embryonic fibroblasts (MEFs) proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg ؊/؊ mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBP␥-deficient newborns die from atelectasis and respiratory failure, which can be mitigated by in utero exposure to the antioxidant N-acetylcysteine. Cebpg ؊/؊ mice on a mixed strain background showed improved viability but, upon aging, developed significantly fewer malignant solid tumors than WT animals. Our findings identify C/EBP␥ as a novel antioxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells.A variety of stresses, such as amino acid limitation, protein misfolding in the endoplasmic reticulum (ER), oxidative stress, hypoxia, and intracellular pathogens, activate gene expression programs collectively known as the integrated stress response (ISR) (1). Stress-induced genes are involved in multiple cellular processes that include nutrient uptake, amino acid synthesis, metabolic changes, antioxidant defenses, and cell survival, leading to cell recovery and alleviation of stress. However, prolonged or irresolvable stress can trigger cell death (2).Protein misfolding and ER stress are associated with several diseases, including diabetes and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Huntington's disease (3). The ISR also plays an important role in cancer as tumor cells frequently experience nutrient deprivation, hypoxia, and oxidative stress and require stress response regulators such as the transcription factor (TF) ATF4 to thrive under adverse conditions (4, 5). Elevated levels of reactive oxygen species (ROS) can initiate oncogenesis by causing DNA mutations and genome instability (6). However, recent studies have shown that, once established, tumor cells are reliant on antioxidant pathways for growth and survival (7,8). Moreover, radio-and chemotherapies induce death or senescence of cancer cells partly by increasing ROS. Thus, acquiring a detailed understanding of the pathways and mechanisms that regulate stress response genes may le...

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Section: Atf4mentioning

confidence: 99%

mentioning

confidence: 99%

C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4

Huggins

Mayekar

Martín

et al. 2016

Molecular and Cellular Biology

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“…Compared with normal cells, many types of cancer cell have increased levels of ROS [17, 20]. Therefore, it might be possible to selectively kill cancer cells by pharmacological ROS insults [21-23]. PLB occurs naturally in the medicinal herb Plumbago zeylanica , which has been safely used for centuries in oriental medicine for treatment of various ailments, including microbial infections and allergic reactions.…”

Section: Discussionmentioning

confidence: 99%

Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Huang

Xie

Pan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Prostate cancer (PCa) is the second most frequently diagnosed cancer in men worldwide. Currently available therapies for hormone-refractory PCa are only marginally effective. Plumbagin (PLB), a natural naphthoquinone isolated from the traditional folk medicine Plumbago zeylanica, is known to selectively kill tumor cells. Nevertheless, antitumor mechanisms initiated by PLB in cancer cells have not been fully defined. Methods: MTT assay was used to evaluate the effect of PLB on the viability of cancer cells. Cell apoptosis and reactive oxygen species (ROS) production were determined by flow cytometry. Protein expression was detected by western blotting. In vivo anti-tumor effect was measured by using tumor xenoqraft model in nude mice. Results: In the present study, we found that PLB decreases cancer cell growth and induces apoptosis in DU145 and PC-3 cells. In addition, by increasing intracellular ROS levels, PLB induced a lethal endoplasmic reticulum stress response in PCa cells. Importantly, blockage of ROS production significantly reversed PLB-induced ER stress activation and cell apoptosis. In vivo, we found that PLB inhibits the growth of PCa xenografts without exhibiting toxicity Treatment of mice bearing human PCa xenografts with PLB was also associated with induction of ER stress activation. Conclusion: Inducing ER stress by PLB thus discloses a previously unrecognized mechanism underlying the biological activity of PLB and provides an in-depth insight into the action of PLB in the treatment of hormone-refractory PCa.

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“…In turn, these antioxidants can be regenerated using the reducing power from the metabolite NADPH, which is generated by multiple metabolic pathways throughout the cell. While the role of ROS in cancer is complex, several recent reports have clearly shown that cellular antioxidant systems are required for multiple steps of tumorigenesis, including tumor initiation [3] and metastasis [4], both of which require anchorage-independent growth. This suggests that the ability to detoxify ROS upon ECM detachment is a critical component of anchorage independence and essential for tumor development and progression.…”

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confidence: 99%

Coping with the metabolic stress of leaving home

Coloff

Brugge

2016

Cell Res

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Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

Cited by 799 publications

References 41 publications

C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4

C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4

Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Coping with the metabolic stress of leaving home

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