Integrated Stress Response Modulates Cellular Redox State via Induction of Cystathionine γ-Lyase

Dickhout, Jeffrey G.; Carlisle, Rachel E.; Jerome, Danielle E.; Mohammed‐Ali, Zahraa; Jiang, Hua; Yang, Guangdong; Mani, Sarathi; Garg, Sanjany K; Banerjee, Ruma; Kaufman, Randal J.; Maclean, Kenneth N.; Wang, Rui; Austin, Richard C.

doi:10.1074/jbc.m111.304576

Cited by 106 publications

(90 citation statements)

References 59 publications

(76 reference statements)

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“…Nrf2 and ATF4 have been found to increase GSH production via multiple mechanisms (44). However, loss of ATF4 impairs GSH production by inhibiting the expression of CTH (45). However, the relevance between TMZ-induced increase of Nrf2 and ATF4 expression and the CTH enzyme regulation, and whether TMZ induced other related enzymes such as CBS (cystathionine β-synthase) in the trans sulfuration pathway for GSH synthesis remain to be clarified and the experiments confirmed.…”

Section: Discussionmentioning

confidence: 82%

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

et al. 2015

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Abstract. Glioblastoma multiforme (GBM) is one of the most common encephalic malignant tumors. Due to a high recurrence rate and a lack of effective treatments, the average survival rate remains low. Temozolomide (TMZ), a class of alkylating agent, is widely used as a first-line therapeutic drug during the adjuvant treatment for GBM patients. However, most patients exhibit a palpable resistance to TMZ treatment. Additionally, the underlying mechanism remains to be clarified. In this study, glutathione (GSH) and reactive oxygen species (ROS) levels were found to be closely associated with the sensitivity of GBM cells to TMZ. We also found that TMZ markedly induced xCT, the subunit of glutamate/cystine transporter system x c -expression, which together with the GSH synthesis was increased while the TMZ-inducible ROS level was decreased in GBM cells. In addition, the cystathionine γ-lyase (CTH) acivity, a key enzyme in the transsulfuration pathway was enhanced by TMZ, which insured a cysteine supply and GSH synthesis in a compensatory manner when xCT was blocked. Thus, the individual inhibition of xCT by siRNA and a pharmacological inhibitor (sulfasalazine) only partially inhibited GSH synthesis and moderately enhanced the GBM cell sensitivity to TMZ. However, the TMZ-induced cytotoxicity was markedly increased along with a marked decrease in GSH levels as result of co-treatment with erastin, which inhibited cysteine uptake from xCT transporter and suppressed CTH activity, leading to impaired transformation from methionine to cysteine. In conclusion, to GBM therapy with a drug combination of TMZ and erastin may be beneficial.

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Section: Discussionmentioning

confidence: 82%

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

et al. 2015

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“…eIF2α signaling has previously been implicated in mediating resistance to oxidative stress (31) by increasing intracellular cysteine and GSH synthesis. Increased cysteine levels are mediated through eIF2α-and ATF4-dependent expression of cystine/glutamate transporter xCT (SLC7A11) (32), a subunit specific to the cystine/glutamate antiporter system Xc − , as well as cystathione γ-lyase (CTH), which produces intracellular cysteine from serine-and homocysteine-derived cystathione (33). We found that, in control cells, xCT and CTH are induced during cyclic hypoxia (Fig.…”

Section: Comparison Of Hif-1 and Eif2α Signaling Pathways On Hypoxiamentioning

confidence: 90%

PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS

Rouschop

Dubois

Keulers

et al. 2013

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

190

147

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Hypoxia is a common feature of tumors and an important contributor to malignancy and treatment resistance. The ability of tumor cells to survive hypoxic stress is mediated in part by hypoxiainducible factor (HIF)-dependent transcriptional responses. More severe hypoxia activates endoplasmatic reticulum stress responses, including the double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)-dependent arm of the unfolded protein response (UPR). Although several studies implicate important roles for HIF and UPR in adaption to hypoxia, their importance for hypoxic cells responsible for therapy resistance in tumors is unknown. By using isogenic models, we find that HIF and eIF2α signaling contribute to the survival of hypoxic cells in vitro and in vivo. However, the eIF2α-dependent arm of the UPR is uniquely required for the survival of a subset of hypoxic cells that determine tumor radioresistance. We demonstrate that eIF2α signaling induces uptake of cysteine, glutathione synthesis, and protection against reactive oxygen species produced during periods of cycling hypoxia. Together these data imply that eIF2α signaling is a critical contributor to the tolerance of therapy-resistant cells that arise as a consequence of transient changes in oxygenation in solid tumors and thus a therapeutic target in curative treatments for solid cancers.growth delay | irradiation | acute hypoxia S olid tumor microenvironments are characterized by extreme heterogeneities in oxygenation that arise as a result of poorly developed vascular networks. Gradients in oxygen are frequently found surrounding perfused vessels, ranging from normal values (∼5%) near the blood vessel to complete anoxia adjacent to necrosis. This gradient of hypoxia is generally referred to as "chronic" or "diffusion-limited" hypoxia and results from cellular oxygen consumption. Hypoxia can also arise in a temporal manner as a consequence of transient changes in oxygen delivery caused by changes in vessel perfusion (1). This "acute" or "perfusion-limited" hypoxia (2) is often cyclic in nature and can account for a large proportion of hypoxic cells at any given time (3). The steady-state proportion of hypoxic cells in tumors is influenced by the tolerance of individual tumor cells to these different types of hypoxia and varies remarkably among tumors with otherwise similar clinical features (4). For example, in head and neck cancer, oxygen electrode measurements of the hypoxic fraction range from 0% to 97% (5). These differences are important, because the fraction of viable hypoxic cells is a major determinant of outcome, as hypoxic cells are highly resistant to chemotherapy and radiation therapy (5, 6). Reducing cellular tolerance to hypoxia is therefore a strategy to reduce the proportion of hypoxic cells in tumors to improve current cancer therapy.The mechanisms influencing hypoxia tolerance and therapy resistance in solid tumors are only partially understood. Hypoxiainducible factor (HIF) ...

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“…Cysteine is also the precursor of sulfur-containing molecules such as taurine and lanthionine, which have cytoprotective functions. In addition to SP1, expression of CSE can also be regulated by the transcription factor, activating transcription factor 4 (ATF4) under conditions of stress (18,19).…”

mentioning

confidence: 99%

Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease

Sbodio

Snyder

Paul

2016

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

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Disturbances in amino acid metabolism, which have been observed in Huntington’s disease (HD), may account for the profound inanition of HD patients. HD is triggered by an expansion of polyglutamine repeats in the protein huntingtin (Htt), impacting diverse cellular processes, ranging from transcriptional regulation to cognitive and motor functions. We show here that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD because of oxidative stress contributed by aberrant cysteine biosynthesis and transport. Consistent with these observations, antioxidant supplementation reverses the disordered ATF4 response to nutrient stress. Our findings establish a molecular link between amino acid disposition and oxidative stress leading to cytotoxicity. This signaling cascade may be relevant to other diseases involving redox imbalance and deficits in amino acid metabolism.

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Integrated Stress Response Modulates Cellular Redox State via Induction of Cystathionine γ-Lyase

Cited by 106 publications

References 59 publications

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS

Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease

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