Understanding cancer metabolism is key to unveil the Achilles’ heel of cancer cells and provide novel therapeutic interventions for patients. While the rerouting of metabolic pathways during development1 or cancer transformation and progression2, 3, 4 has been extensively characterised, the exact dynamic of these events, their distribution and frequency in the different tumour types, and the correlation with genetic background remain largely unknown. In a recent article published in Nature, Karen Vousden’s team assesses the effect of serine and glycine dietary restriction in autochthonous mouse tumour models driven by different oncogenes (Maddocks et al, 2017)5, leading to potential area of therapeutic intervention

B Chaneton

Christian Frezza

EC Cheung

EH Ma

F Kottakis

Gerry Melino

GM DeNicola

I Amelio

Ivano Amelio

J Ye

JW Locasale

K Zaugg

M Agostini

M Sciacovelli

M Yang

OD Maddocks

ODK Maddocks

P Lee

R Possemato

VD Longo

Amelio, Ivano

Melino, Gennaro

Frezza, Christian

Exploiting tumour addiction with a serine and glycine-free diet

Melino, Gerry

Repository@Nottingham

OPENNews and CommentaryExploiting tumour addiction with a serine andglycine-free dietIvano Amelio*,1, Gerry Melino1,2 and Christian Frezza3Cell Death and Differentiation (2017) 24, 1311–1313; doi:10.1038/cdd.2017.83; published online 2 June 2017Understanding cancer metabolism is key to revealing theAchilles’ heel of cancer cells and providing novel therapeuticinterventions for patients. While the rerouting of metabolicpathways during development1 or cancer transformation andprogression2–4 has been extensively characterised, the exactdynamics of these events, their distribution and frequency indifferent tumour types, and their correlation with geneticbackground remain largely unknown. In a recent articlepublished inNature, Karen Vousden’s team assesses the effectof serine and glycine (SG) dietary restriction in autochthonousmouse tumour models driven by different oncogenes,5 leadingto potential areas of therapeutic intervention.The non-essential amino acids serine and glycine are nowconsidered essential metabolites for some types of cancers.3,6Serine can be imported into the cell through differenttransporters or can be produced by diversion of glycolyticglucose in the serine biosynthetic pathway (SSP).7 Exogen-ous or de novo-synthetised serine is converted to glycine, andby stimulating one-carbon metabolism, provides a source ofnucleotides, ATP, methylation reactions, and antioxidantdefences, such as glutathione and NAPDH.8 Cancer cellscan react to SG deprivation by triggering SSP, suppressingaerobic glycolysis, and increasing the flux to the tricarboxylicacid cycle. This rearrangement of metabolism supportsadaptation to oxidative stress initiated by impaired one-carbon metabolism, and allows cells to survive under theseadverse conditions. Notably, the response to serine starvationis regulated by p53 and, in consequence, p53− /− cells fail torespond to SG depletion, showing severe impairment ofproliferation and cell viability associated with unbalancedredox defence.9 Together, these lines of research indicate thatSG metabolism can be a potential target for cancer therapy.As an alternative to selectively targeting the enzymesresponsible for SG synthesis, Maddocks et al.5 reasoned thatSG deprivation could be a powerful strategy to affect thispathway. In their recent study, they analysed the response toan SG-free diet in different genetically modified animal modelsof lymphoma (Eμ-Myc), intestinal tumours (ApcMin/+), andpancreatic cancer (Pdx1-cre; KRasG12D/+; trp53+/− and Pdx1-cre; KRasG12D/+; Trp53R172H/+). These experiments indicatedthat SG starvation effectively prolongs survival of Eμ-Myc andApcMin/+mice, which carry pre-malignant lesions since shortlyafter birth. The authors also tested the impact of this restricteddiet on established malignant tumours. They developedxenograft/allograft models by subcutaneous injection ofhuman colorectal carcinoma (HCT-116) or mouse Eμ-Myctumour cells and transferred the animals to an SG-depletedexperimental diet after the tumours were established. SGrestriction reduced tumour volume after relatively shortperiods of treatment (6 days of SG-free diet in Eμ-Myc cells-derived tumours) and this was associated with increased celldeath in the tumour core.SG deprivation was also shown to increase mitochondrialmetabolism.10 Therefore, the authors tested the effects of SGdietary restriction in combination with biguanides and inhibi-tors of complex I of the electron transport chain. The resultshighlighted a complex response that suggested that bigua-nides and SG deprivationmight synergise in restricting tumourgrowth when the combination effectively prevents oxidativedefence. Phenoformin indeed reduced tumour growth inEμ-Myc mice. However, due to its high toxicity, the use of themore tolerable analogue metformin was required to completethe study. Unexpectedly, in SG-deprived ApcMin/+mice, phar-macological doses of metformin promoted tumour growthrather than improving the anti-tumour effect. Remarkably, low-and high-dose metformin correlated with increased ordecreased reactive oxygen species (ROS) levels, respec-tively, indicating that the ability of metformin to synergise withSG depletion correlates with its anti- or pro-oxidant effects. Toformally prove that increased ROS levels enhance anti-tumoureffects of the SG-free diet, the authors crossed Eμ-Myc micewith mice deficient for Tigar, a fructose-2,6-bisphosphatase,which limits glycolysis and favours pentose phosphate path-ways, thus limiting ROS levels11,12 (Figure 1). The combina-tion of Tigar deficiency and SG deprivation significantlyincreased overall survival with an additive effect. As a commonmechanism of action of routine chemotherapeutic drugs is toattack the cancer cells with high levels of ROS, it is now apriority to test whether an SG-free diet improves efficacy ofstandard anticancer therapies.The authors then tested the effects of SG deprivation on amodel of pancreatic cancer driven by K-Ras mutation.Surprisingly, the authors found that SG restriction did notaffect tumour growth and survival in two different models ofKras-driven pancreatic tumours (Pdx1-cre; KRasG12D/+;trp53+/−and Pdx1-cre; KRasG12D/+; Trp53R172H/+). Further1MRC Toxicology Unit, Leicester, UK; 2Department Experimental Medicine & Surgery, University Rome Tor Vergata, Rome, Italy and 3MRC Cancer Unit, Cambridge, UK*Corresponding author: I Amelio, MRC Toxicology Unit, Hodgkin Building Lancaster Road, Leicester LE1 9HN, UK. Tel: +44-116-3-252 5564; +44(0)116 252 5599;E-mail: ia119@le.ac.ukCell Death and Differentiation (2017) 24, 1311–1313Official journal of the Cell Death Differentiation Associationwww.nature.com/cddanalysis showed that these Kras-driven tumour models relyheavily on SSP for SG supply, when compared to intestinalApcMin/+ cancers. Analysis of intravenously injected 13C-15N-labelled serine in mice revealed that pancreatic tumours takeup serine and glycine at a similar level to healthy pancreas;conversely, serine uptake in ApcMin/+ tumours is significantlyincreased as compared to normal intestinal tissues.Accordingly, KrasG12D-expressing cells had high levels ofSSPenzymes (PHGDH, PAST1, and PSPH), and depletion ofKras reduced their expression (Figure 1). Expression ofKrasG12D in organoids derived from Vil1-creER;APCfl/fl intest-inal tumours promoted conversion of glucose to serine andthus restored their in vitro growth upon exogenous SGdeprivation. These data are in agreement with a recent studyFigure 1 The serine synthesis pathway (SSP) diverges from glycolysis utilising the intermediate 3P-glycerate, which is converted by PHGDH, PSAT-1, and PSPH into serineand then glycine. Removal of exogenous serine and glycine causes activation of SSP, however Vousden’s study demonstrates that tumours, such as Eμ-Myc- and ApcMin/+-drivenlymphomas and intestinal lesions can be susceptible to serine and glycine (SG) deprivation. Concurrent SG dietary restriction and biguanide administration might improveanti-tumour effects when associated with a reduction in antioxidant defence. On contrary, Kras-driven pancreatic tumours appear resistant to SG-free diet as observed from theability of Kras to promote expression of PHGDH, PSAT-1, and PSPH and thus boost activity of SSP. This figure is re-adapted from Amelio and Melino19News and Commentary1312Cell Death and Differentiationby Kottakis et al.13 reporting that concurrent Krasmutation andLKB1 depletion in the pancreas drives upregulation of SSPand dependence of these cells on this biosynthetic pathway.In conclusion, these study data highlight the complexity ofSG metabolism in cancer cells and the importance of themutational landscape of cancer in the response to dietaryrestriction and therapeutic intervention. Indeed, SG depriva-tion could be ineffective in tumours that exhibit an active SSP.However, in Kras-driven tumours, the effects of SG restrictioncould be limited in breast tumours characterised by PHGDHamplification,14,15 but also in lung tumours, where NRF2 wasshown to activate SSP.16 Another important aspect is that theeffects of SG deprivation depends on the redox status of thecell. Although the role of oxidative stress in cancer is currentlyhighly debated, this work shows that the effects of SGdeprivation could be potentially compromised by strategiesthat prevent oxidative stress, such as antioxidants. Therefore,any dietary intervention needs to be fine-tuned to preventidiosyncratic interactions. This work raises several interestingquestions. For instance, it will be interesting to assesswhetherSG-free diets can prevent tumour formation, in addition toslowing its progression. In this context, it is intriguing tospeculate that the anticancer effects of low-protein diets orcalorie restriction17 are, at least in part, mediated by SGrestriction. Finally, it will be important to assess the mechan-isms beyond the anticancer effects of SG starvation. AnSG-free diet affects the immune system leading to adysregulation of T lymphocytes, as recently suggested.18 Itwill be interesting to determine whether this diet, besidesexhibiting cell-autonomous effects, can actually modulate theimmune system to fight cancer cells.Conflict of InterestThe authors declare no conflict of interest.1. Agostini M et al. Cell Death Differ 2016; 23: 1502–1514.2. Zaugg K et al. Genes Dev 2011; 25: 1041–1051.3. Sciacovelli M et al. Nature 2016; 537: 544–547.4. Sciacovelli M, Frezza C. Cell Death Differ 2017; 24: 1–2.5. Maddocks ODK et al. Nature 2017; 544: 372–376.6. Ye J et al. Proc Natl Acad Sci USA 2012; 109: 6904–6909.7. Amelio I et al. Trends Biochem Sci 2014; 39: 191–198.8. Yang M, Vousden KH. Nat Rev Cancer 2016; 16: 650–662.9. Maddocks OD et al. Nature 2013; 493: 542–546.10. Chaneton B et al. Nature 2012; 491: 458–462.11. Lee P et al. Cancer Metab 2014; 2: 1.12. Cheung EC et al. Dev Cell 2013; 25: 463–477.13. Kottakis F et al. Nature 2016; 539: 390–395.14. Possemato R et al. Nature 2011; 476: 346–350.15. Locasale JW et al. Nat Genet 2011; 43: 869–874.16. DeNicola GM et al. Nat Genet 2015; 47: 1475–1481.17. Longo VD et al. Trends Pharmacol Sci 2010; 31: 89–98.18. Ma EH et al. Cell Metab 2017; 25: 345–357.19. Amelio I, Melino G. Trends Biochem Sci 2015; 40: 425–434.This work is licensed under a Creative CommonsAttribution-NonCommercial-ShareAlike 4.0 InternationalLicense. The images or other third party material in this article areincluded in the article’s Creative Commons license, unless indicatedotherwise in the credit line; if the material is not included under theCreative Commons license, users will need to obtain permission fromthe license holder to reproduce the material. To view a copy of thislicense, visit http://creativecommons.org/licenses/by-nc-sa/4.0/r The Author(s) 2017News and Commentary1313Cell Death and Differentiation

English

KOPS - The Institutional Repository of the University of Konstanz

Crossref

Cell Death and Differentiation

Apollo (Cambridge)

OPENNews and CommentaryExploiting tumour addiction with a serine andglycine-free dietIvano Amelio*,1, Gerry Melino1,2 and Christian Frezza3Cell Death and Differentiation (2017) 24, 1311–1313; doi:10.1038/cdd.2017.83; published online 2 June 2017Understanding cancer metabolism is key to revealing theAchilles’ heel of cancer cells and providing novel therapeuticinterventions for patients. While the rerouting of metabolicpathways during development1 or cancer transformation andprogression2–4 has been extensively characterised, the exactdynamics of these events, their distribution and frequency indifferent tumour types, and their correlation with geneticbackground remain largely unknown. In a recent articlepublished inNature, Karen Vousden’s team assesses the effectof serine and glycine (SG) dietary restriction in autochthonousmouse tumour models driven by different oncogenes,5 leadingto potential areas of therapeutic intervention.The non-essential amino acids serine and glycine are nowconsidered essential metabolites for some types of cancers.3,6Serine can be imported into the cell through differenttransporters or can be produced by diversion of glycolyticglucose in the serine biosynthetic pathway (SSP).7 Exogen-ous or de novo-synthetised serine is converted to glycine, andby stimulating one-carbon metabolism, provides a source ofnucleotides, ATP, methylation reactions, and antioxidantdefences, such as glutathione and NAPDH.8 Cancer cellscan react to SG deprivation by triggering SSP, suppressingaerobic glycolysis, and increasing the flux to the tricarboxylicacid cycle. This rearrangement of metabolism supportsadaptation to oxidative stress initiated by impaired one-carbon metabolism, and allows cells to survive under theseadverse conditions. Notably, the response to serine starvationis regulated by p53 and, in consequence, p53− /− cells fail torespond to SG depletion, showing severe impairment ofproliferation and cell viability associated with unbalancedredox defence.9 Together, these lines of research indicate thatSG metabolism can be a potential target for cancer therapy.As an alternative to selectively targeting the enzymesresponsible for SG synthesis, Maddocks et al.5 reasoned thatSG deprivation could be a powerful strategy to affect thispathway. In their recent study, they analysed the response toan SG-free diet in different genetically modified animal modelsof lymphoma (Eμ-Myc), intestinal tumours (ApcMin/+), andpancreatic cancer (Pdx1-cre; KRasG12D/+; trp53+/− and Pdx1-cre; KRasG12D/+; Trp53R172H/+). These experiments indicatedthat SG starvation effectively prolongs survival of Eμ-Myc andApcMin/+mice, which carry pre-malignant lesions since shortlyafter birth. The authors also tested the impact of this restricteddiet on established malignant tumours. They developedxenograft/allograft models by subcutaneous injection ofhuman colorectal carcinoma (HCT-116) or mouse Eμ-Myctumour cells and transferred the animals to an SG-depletedexperimental diet after the tumours were established. SGrestriction reduced tumour volume after relatively shortperiods of treatment (6 days of SG-free diet in Eμ-Myc cells-derived tumours) and this was associated with increased celldeath in the tumour core.SG deprivation was also shown to increase mitochondrialmetabolism.10 Therefore, the authors tested the effects of SGdietary restriction in combination with biguanides and inhibi-tors of complex I of the electron transport chain. The resultshighlighted a complex response that suggested that bigua-nides and SG deprivationmight synergise in restricting tumourgrowth when the combination effectively prevents oxidativedefence. Phenoformin indeed reduced tumour growth inEμ-Myc mice. However, due to its high toxicity, the use of themore tolerable analogue metformin was required to completethe study. Unexpectedly, in SG-deprived ApcMin/+mice, phar-macological doses of metformin promoted tumour growthrather than improving the anti-tumour effect. Remarkably, low-and high-dose metformin correlated with increased ordecreased reactive oxygen species (ROS) levels, respec-tively, indicating that the ability of metformin to synergise withSG depletion correlates with its anti- or pro-oxidant effects. Toformally prove that increased ROS levels enhance anti-tumoureffects of the SG-free diet, the authors crossed Eμ-Myc micewith mice deficient for Tigar, a fructose-2,6-bisphosphatase,which limits glycolysis and favours pentose phosphate path-ways, thus limiting ROS levels11,12 (Figure 1). The combina-tion of Tigar deficiency and SG deprivation significantlyincreased overall survival with an additive effect. As a commonmechanism of action of routine chemotherapeutic drugs is toattack the cancer cells with high levels of ROS, it is now apriority to test whether an SG-free diet improves efficacy ofstandard anticancer therapies.The authors then tested the effects of SG deprivation on amodel of pancreatic cancer driven by K-Ras mutation.Surprisingly, the authors found that SG restriction did notaffect tumour growth and survival in two different models ofKras-driven pancreatic tumours (Pdx1-cre; KRasG12D/+;trp53+/−and Pdx1-cre; KRasG12D/+; Trp53R172H/+). Further1MRC Toxicology Unit, Leicester, UK; 2Department Experimental Medicine & Surgery, University Rome Tor Vergata, Rome, Italy and 3MRC Cancer Unit, Cambridge, UK*Corresponding author: I Amelio, MRC Toxicology Unit, Hodgkin Building Lancaster Road, Leicester LE1 9HN, UK. Tel: +44-116-3-252 5564; +44(0)116 252 5599;E-mail: ia119@le.ac.ukCell Death and Differentiation (2017) 24, 1311–1313Ofﬁcial journal of the Cell Death Differentiation Associationwww.nature.com/cddanalysis showed that these Kras-driven tumour models relyheavily on SSP for SG supply, when compared to intestinalApcMin/+ cancers. Analysis of intravenously injected 13C-15N-labelled serine in mice revealed that pancreatic tumours takeup serine and glycine at a similar level to healthy pancreas;conversely, serine uptake in ApcMin/+ tumours is significantlyincreased as compared to normal intestinal tissues.Accordingly, KrasG12D-expressing cells had high levels ofSSPenzymes (PHGDH, PAST1, and PSPH), and depletion ofKras reduced their expression (Figure 1). Expression ofKrasG12D in organoids derived from Vil1-creER;APCfl/fl intest-inal tumours promoted conversion of glucose to serine andthus restored their in vitro growth upon exogenous SGdeprivation. These data are in agreement with a recent studyFigure 1 The serine synthesis pathway (SSP) diverges from glycolysis utilising the intermediate 3P-glycerate, which is converted by PHGDH, PSAT-1, and PSPH into serineand then glycine. Removal of exogenous serine and glycine causes activation of SSP, however Vousden’s study demonstrates that tumours, such as Eμ-Myc- and ApcMin/+-drivenlymphomas and intestinal lesions can be susceptible to serine and glycine (SG) deprivation. Concurrent SG dietary restriction and biguanide administration might improveanti-tumour effects when associated with a reduction in antioxidant defence. On contrary, Kras-driven pancreatic tumours appear resistant to SG-free diet as observed from theability of Kras to promote expression of PHGDH, PSAT-1, and PSPH and thus boost activity of SSP. This figure is re-adapted from Amelio and Melino19News and Commentary1312Cell Death and Differentiationby Kottakis et al.13 reporting that concurrent Krasmutation andLKB1 depletion in the pancreas drives upregulation of SSPand dependence of these cells on this biosynthetic pathway.In conclusion, these study data highlight the complexity ofSG metabolism in cancer cells and the importance of themutational landscape of cancer in the response to dietaryrestriction and therapeutic intervention. Indeed, SG depriva-tion could be ineffective in tumours that exhibit an active SSP.However, in Kras-driven tumours, the effects of SG restrictioncould be limited in breast tumours characterised by PHGDHamplification,14,15 but also in lung tumours, where NRF2 wasshown to activate SSP.16 Another important aspect is that theeffects of SG deprivation depends on the redox status of thecell. Although the role of oxidative stress in cancer is currentlyhighly debated, this work shows that the effects of SGdeprivation could be potentially compromised by strategiesthat prevent oxidative stress, such as antioxidants. Therefore,any dietary intervention needs to be fine-tuned to preventidiosyncratic interactions. This work raises several interestingquestions. For instance, it will be interesting to assesswhetherSG-free diets can prevent tumour formation, in addition toslowing its progression. In this context, it is intriguing tospeculate that the anticancer effects of low-protein diets orcalorie restriction17 are, at least in part, mediated by SGrestriction. Finally, it will be important to assess the mechan-isms beyond the anticancer effects of SG starvation. AnSG-free diet affects the immune system leading to adysregulation of T lymphocytes, as recently suggested.18 Itwill be interesting to determine whether this diet, besidesexhibiting cell-autonomous effects, can actually modulate theimmune system to fight cancer cells.Conflict of InterestThe authors declare no conflict of interest.1. Agostini M et al. Cell Death Differ 2016; 23: 1502–1514.2. Zaugg K et al. Genes Dev 2011; 25: 1041–1051.3. Sciacovelli M et al. Nature 2016; 537: 544–547.4. Sciacovelli M, Frezza C. Cell Death Differ 2017; 24: 1–2.5. Maddocks ODK et al. Nature 2017; 544: 372–376.6. Ye J et al. Proc Natl Acad Sci USA 2012; 109: 6904–6909.7. Amelio I et al. Trends Biochem Sci 2014; 39: 191–198.8. Yang M, Vousden KH. Nat Rev Cancer 2016; 16: 650–662.9. Maddocks OD et al. Nature 2013; 493: 542–546.10. Chaneton B et al. Nature 2012; 491: 458–462.11. Lee P et al. Cancer Metab 2014; 2: 1.12. Cheung EC et al. Dev Cell 2013; 25: 463–477.13. Kottakis F et al. Nature 2016; 539: 390–395.14. Possemato R et al. Nature 2011; 476: 346–350.15. Locasale JW et al. Nat Genet 2011; 43: 869–874.16. DeNicola GM et al. Nat Genet 2015; 47: 1475–1481.17. Longo VD et al. Trends Pharmacol Sci 2010; 31: 89–98.18. Ma EH et al. Cell Metab 2017; 25: 345–357.19. Amelio I, Melino G. Trends Biochem Sci 2015; 40: 425–434.This work is licensed under a Creative CommonsAttribution-NonCommercial-ShareAlike 4.0 InternationalLicense. The images or other third party material in this article areincluded in the article’s Creative Commons license, unless indicatedotherwise in the credit line; if the material is not included under theCreative Commons license, users will need to obtain permission fromthe license holder to reproduce the material. To view a copy of thislicense, visit http://creativecommons.org/licenses/by-nc-sa/4.0/r The Author(s) 2017News and Commentary1313Cell Death and Differentiation

Exploiting tumour addiction with a serine and glycine-free diet.

https://nottingham-repository.worktribe.com/4235768/1/cdd201783

Exploiting tumour addiction with a serine and glycine-free diet.

Abstract

Similar works

Full text

Available Versions

ART

Repository@Nottingham

KOPS - The Institutional Repository of the University of Konstanz

Crossref

Apollo (Cambridge)