Polyamine pathway activity promotes cysteine essentiality in cancer cells

Zhang, Tong; Bauer, Christin; Newman, Alice C.; Uribe, Alejandro Huerta; Athineos, Dimitris; Blyth, Karen; Maddocks, Oliver D.K.

doi:10.1038/s42255-020-0253-2

Cited by 37 publications

(46 citation statements)

References 56 publications

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“…Then, in nutrient-limited conditions, cystathionine can be broken down to yield cysteine. The disconnection between the TS pathway and the methionine cycle was reported recently in similar experiments that found that after addition of either cystathionine or homocysteine, both proliferation and recovery were restored, but not when cells were supplemented with methionine in a cysteine-deficient medium (47).…”

Section: Discussionmentioning

confidence: 52%

Cysteine is a limiting factor for glioma proliferation and survival

Larion

Ruiz‐Rodado

Dowdy

et al. 2021

Preprint

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Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. We report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. 13C-tracing and the analysis of cystathionine synthase and cystathioninase levels revealed the metabolic landscape attributable to cysteine deprivation, and the disconnection between the methionine cycle and the transsulfuration pathway. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, with concomitant reductions in glutathione and cysteine plasma levels. At the end point, however, tumors displayed the ability to synthesize glutathione, although higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolites in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

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Section: Discussionmentioning

confidence: 52%

Cysteine is a limiting factor for glioma proliferation and survival

Larion

Ruiz‐Rodado

Dowdy

et al. 2021

Preprint

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“…This may be because ascorbate (also known as Vitamin C) is an effective antioxidant used to detoxify reactive oxygen species (ROS). ROS are a byproduct of many metabolic reactions such as oxidative phosphorylation and methionine metabolism, which indirectly produces ROS by supporting polyamine synthesis [10]. Indeed, the sensitivity to inhibitors of Ascorbate and Aldarate metabolism is stronger when expression of these ROS producing pathways is high ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For example, leukemias and gliomas with mutations in isocitrate dehydrogenase (IDH) are sensitive to inhibitors specific to mutant IDH [8,9]. In addition, some tumors are sensitive to depletion or restriction of amino acids, including cysteine in tumors with deleted methylthioadenosine phosphorylase ( MTAP ) [10], serine in tumors with deleted p53 ( TP53 ) [11], asparagine in leukemias with low expression of asparagine synthetase ( ASNS ) [12], asparagine in tumors with inhibition of the electron transport chain [13], and methionine in RAS-driven tumors [14]. Other efforts have identified metabolic vulnerabilities related to redox balance including in cancer cells with dysregulated PI3K/AKT signaling [15] or overexpression of the L-glutamate/L-cystine antiporter SLC7A11 [16,17].…”

Section: Introductionmentioning

confidence: 99%

The landscape of metabolic pathway dependencies in cancer cell lines

Joly

Chew

Graham

2020

Preprint

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The metabolic reprogramming of cancer cells creates metabolic vulnerabilities that can be therapeutically targeted. However, our understanding of metabolic dependencies and the pathway crosstalk that creates these vulnerabilities in cancer cells remains incomplete. Here, by integrating gene expression data with genetic loss-of-function and pharmacological screening data from hundreds of cancer cell lines, we identified metabolic vulnerabilities at the level of pathways rather than individual genes. This approach revealed that metabolic pathway dependencies are highly context-specific such cancer cells are vulnerable to inhibition of one metabolic pathway only when activity of another metabolic pathway is altered. Notably, we also found that the no single metabolic pathway was universally essential, suggesting that cancer cells are not invariably dependent on any metabolic pathway. In addition, we confirmed that cell culture medium is a major confounding factor for the analysis of metabolic pathway vulnerabilities. Nevertheless, we found robust associations between metabolic pathway activity and sensitivity to clinically approved drugs that were independent of cell culture medium. Lastly, we used parallel integration of pharmacological and genetic dependency data to confidently identify metabolic pathway vulnerabilities. Taken together, this study serves as a comprehensive characterization of the landscape of metabolic pathway vulnerabilities in cancer cell lines.

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“…Interestingly, a recent study by Zhang and colleagues [119] showed that there was a strong correlation between efflux of the polyamine synthesis byproduct MTA and sensitivity to cysteine starvation. In fact, inhibition of polyamine biosynthesis by treatment with an AMD1 inhibitor (sardomozide) or with MTOB (4-methyylthio-2-oxobutanoic acid), an intermediate in the methionine salvage pathway [120,121] (Figure 1), rescues cysteine-dependent cells from cysteine starvation [119]. In contrast, polyamine supplementation increase ROS levels and sensitizes these cells to cysteine starvation, and these effects are blocked by inhibition of SMOX and PAOX.…”

Section: Control Of Polyamine Homeostasis and Interacting Metabolic Pathways In Cancermentioning

confidence: 99%

“…In contrast, polyamine supplementation increase ROS levels and sensitizes these cells to cysteine starvation, and these effects are blocked by inhibition of SMOX and PAOX. Finally, MTAP-deleted cells exhibited strong sensitivity to cysteine starvation where loss of MTAP leads to increased AMD1 expression, polyamine levels, ROS and cell death [119].…”

Section: Control Of Polyamine Homeostasis and Interacting Metabolic Pathways In Cancermentioning

confidence: 99%

Polyamine Homeostasis in Development and Disease

Nakanishi

Cleveland

2021

Medical Sciences

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Polycationic polyamines are present in nearly all living organisms and are essential for mammalian cell growth and survival, and for development. These positively charged molecules are involved in a variety of essential biological processes, yet their underlying mechanisms of action are not fully understood. Several studies have shown both beneficial and detrimental effects of polyamines on human health. In cancer, polyamine metabolism is frequently dysregulated, and elevated polyamines have been shown to promote tumor growth and progression, suggesting that targeting polyamines is an attractive strategy for therapeutic intervention. In contrast, polyamines have also been shown to play critical roles in lifespan, cardiac health and in the development and function of the brain. Accordingly, a detailed understanding of mechanisms that control polyamine homeostasis in human health and disease is needed to develop safe and effective strategies for polyamine-targeted therapy.

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Polyamine pathway activity promotes cysteine essentiality in cancer cells

Cited by 37 publications

References 56 publications

Cysteine is a limiting factor for glioma proliferation and survival

Cysteine is a limiting factor for glioma proliferation and survival

The landscape of metabolic pathway dependencies in cancer cell lines

Polyamine Homeostasis in Development and Disease

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