mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Amaia Zabala-Letona; Amaia Arruabarrena-Aristorena; Natalia Martín-Martín; Sonia Fernandez-Ruiz; James D Sutherland; Michelle Clasquin; Julen Tomas-Cortazar; Jose Jimenez; Ines Torres; Phong Quang; Pilar Ximenez-Embun; Ruzica Bago; Aitziber Ugalde-Olano; Ana Loizaga-Iriarte; Isabel Lacasa-Viscasillas; Miguel Unda; Verónica Torrano; Diana Cabrera; Sebastiaan M van Liempd; Ylenia Cendon; Elena Polentinos-Castro; Stuart Murray; Ajinkya Revandkar; Andrea Alimonti; Yinan Zhang; Amelia Barnett; Gina Lein; David Pirman; Ana R Cortazar; Leire Arreal; Ludmila Prudkin; Ianire Astobiza; Lorea Valcarcel-Jimenez; Patricia Zuñiga-García; Itziar Fernandez-Dominguez; Marco Piva; Alfredo Caro-Maldonado; Pilar Sánchez-Mosquera; Mireia Castillo-Martín; Violeta Serra; Naiara Beraza; Antonio Gentilella; George Thomas; Mikel Azkargorta; Felix Elortza; Rosa Farràs; David Olmos; Alejo Efeyan; Juan Anguita; Javier Muñoz; Juan M Falcón-Pérez; Rosa Barrio; Teresa Macarulla; Jose M Mato; Maria L Martinez-Chantar; Carlos Cordon-Cardo; Ana M Aransay; Kevin Marks; José Baselga; Josep Tabernero; Paolo Nuciforo; Brendan D Manning; Katya Marjon; Arkaitz Carracedo

doi:10.1038/nature22964

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Natalia Martín-Martín, Sonia Fernandez-Ruiz, James D Sutherland, Michelle Clasquin, Julen Tomas-Cortazar, Jose Jimenez, Ines Torres, Phong Quang, Pilar Ximenez-Embun, Ruzica Bago, Aitziber Ugalde-Olano, Ana Loizaga-Iriarte, Isabel Lacasa-Viscasillas, Miguel Unda, Verónica Torrano, Diana Cabrera, Sebastiaan M van Liempd, Ylenia CendonElena Polentinos-Castro, Stuart Murray, Ajinkya Revandkar, Andrea Alimonti, Yinan Zhang, Amelia Barnett, Gina Lein, David Pirman, Ana R Cortazar, Leire Arreal, Ludmila Prudkin, Ianire Astobiza, Lorea Valcarcel-Jimenez, Patricia Zuñiga-García, Itziar Fernandez-Dominguez, Marco Piva, Alfredo Caro-Maldonado, Pilar Sánchez-Mosquera, Mireia Castillo-Martín, Violeta Serra, Naiara Beraza, Antonio Gentilella, George Thomas, Mikel Azkargorta, Felix Elortza, Rosa Farràs, David Olmos, Alejo Efeyan, Juan Anguita, Javier Muñoz, Juan M Falcón-Pérez, Rosa Barrio, Teresa Macarulla, Jose M Mato, Maria L Martinez-Chantar, Carlos Cordon-Cardo, Ana M Aransay, Kevin Marks, José Baselga, Josep Tabernero, Paolo Nuciforo, Brendan D Manning, Katya Marjon, Arkaitz Carracedo (Lead / Corresponding author)

Research output: Contribution to journal › Letter › peer-review

157 Citations (Scopus)

Abstract

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

Original language	English
Pages (from-to)	109-113
Number of pages	22
Journal	Nature
Volume	547
Issue number	7661
Early online date	28 Jun 2017
DOIs	https://doi.org/10.1038/nature22964
Publication status	Published - 6 Jul 2017

Keywords

Journal article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Zabala-Letona, A., Arruabarrena-Aristorena, A., Martín-Martín, N., Fernandez-Ruiz, S., Sutherland, J. D., Clasquin, M., Tomas-Cortazar, J., Jimenez, J., Torres, I., Quang, P., Ximenez-Embun, P., Bago, R., Ugalde-Olano, A., Loizaga-Iriarte, A., Lacasa-Viscasillas, I., Unda, M., Torrano, V., Cabrera, D., van Liempd, S. M., ... Carracedo, A. (2017). mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature, 547(7661), 109-113. https://doi.org/10.1038/nature22964

@article{367f84f46a564aee96843e94f2187824,

title = "mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer",

abstract = "Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.",

keywords = "Journal article",

author = "Amaia Zabala-Letona and Amaia Arruabarrena-Aristorena and Natalia Mart{\'i}n-Mart{\'i}n and Sonia Fernandez-Ruiz and Sutherland, {James D} and Michelle Clasquin and Julen Tomas-Cortazar and Jose Jimenez and Ines Torres and Phong Quang and Pilar Ximenez-Embun and Ruzica Bago and Aitziber Ugalde-Olano and Ana Loizaga-Iriarte and Isabel Lacasa-Viscasillas and Miguel Unda and Ver{\'o}nica Torrano and Diana Cabrera and {van Liempd}, {Sebastiaan M} and Ylenia Cendon and Elena Polentinos-Castro and Stuart Murray and Ajinkya Revandkar and Andrea Alimonti and Yinan Zhang and Amelia Barnett and Gina Lein and David Pirman and Cortazar, {Ana R} and Leire Arreal and Ludmila Prudkin and Ianire Astobiza and Lorea Valcarcel-Jimenez and Patricia Zu{\~n}iga-Garc{\'i}a and Itziar Fernandez-Dominguez and Marco Piva and Alfredo Caro-Maldonado and Pilar S{\'a}nchez-Mosquera and Mireia Castillo-Mart{\'i}n and Violeta Serra and Naiara Beraza and Antonio Gentilella and George Thomas and Mikel Azkargorta and Felix Elortza and Rosa Farr{\`a}s and David Olmos and Alejo Efeyan and Juan Anguita and Javier Mu{\~n}oz and Falc{\'o}n-P{\'e}rez, {Juan M} and Rosa Barrio and Teresa Macarulla and Mato, {Jose M} and Martinez-Chantar, {Maria L} and Carlos Cordon-Cardo and Aransay, {Ana M} and Kevin Marks and Jos{\'e} Baselga and Josep Tabernero and Paolo Nuciforo and Manning, {Brendan D} and Katya Marjon and Arkaitz Carracedo",

note = "Funding: Ram{\'o}n y Cajal award (to A.C., A.E., J.M., D.O.), Juan de la Cierva (to E.C., A.C.-M.), BFU grant (to R.B.: BFU2014-52282-P and BFU2011-25986), SAF grant (to A.C.: SAF2016-79381-R, FEDER/EU; M.L.M.-C.: SAF2014-54658-R; to J.M.F.-P.: SAF2015-66312; to J.M.M: SAF 2014-52097R; to A.E.: SAF2015-67538-R; to J.A.: SAF2015-65327R; to G.T.: SAF2011-24967) from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO); European Union (to A.C.: ERC-StG-336343, PoC754627; to A.C.-M.: CIG 660191; to J.A.: 602272; to A.E.: ERC-2014-STG-638891); Basque Government Department of Health (to V.T.: 2016111109; to J.M.F.-P: 2015111149), Department of Education (to A.C.: PI2012/03 and IKERTALDE I.T.1106-16; to R.B.: PI2012/42; to M.L.M.-C.: 2013) and PhD grants (to A.A.-A. and L.V.-J.); AECC (to V.T.: 2016 JP Bizkaia; to N.M.-M.: 2011 JP Bizkaia; to M.L.M.-C.); ISCIII (to A.C.: PI10/01484, PI13/00031; to J.M.: Proteored PR.B.2 and grant PT13/0001; to R.F.: PI15/209; to V.S.: PI13/01714, CP14/00228); Ram{\'o}n Areces foundation (to J.M.F.-P.); Basque Department of Industry, Tourism and Trade (Etortek) (to A.C.); FERO Foundation (to A.C., V.S.); Fundaci{\'o}n Vasca de Innovaci{\'o}n e Investigaci{\'o}n Sanitarias, BIOEF (to V.T.: BIO15/CA/052); BBVA Foundation (to A.C.; P.N. team); National Institutes of Health (to C.C.-C. and M.C.: P01CA087497; to J.M.M.: R01AT001576); Fundaci{\'o}n CRIS contra el C{\'a}ncer (to D.O. team); 2014 Stewart Rahr Young Investigator Award from the Prostate Cancer Foundation (to D.O.); FPU predoctoral fellowship (to Y.C.: 15/05126); Catalan Agency AGAUR (to V.S.: 2014 SGR 1331); Medical Research Council (to R. Bago, D. Alessi laboratory: grant number MC_UU_12016/2). The activity of CIBERONC was co-funded with FEDER funds.",

year = "2017",

month = jul,

day = "6",

doi = "10.1038/nature22964",

language = "English",

volume = "547",

pages = "109--113",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7661",

}

Zabala-Letona, A, Arruabarrena-Aristorena, A, Martín-Martín, N, Fernandez-Ruiz, S, Sutherland, JD, Clasquin, M, Tomas-Cortazar, J, Jimenez, J, Torres, I, Quang, P, Ximenez-Embun, P, Bago, R, Ugalde-Olano, A, Loizaga-Iriarte, A, Lacasa-Viscasillas, I, Unda, M, Torrano, V, Cabrera, D, van Liempd, SM, Cendon, Y, Polentinos-Castro, E, Murray, S, Revandkar, A, Alimonti, A, Zhang, Y, Barnett, A, Lein, G, Pirman, D, Cortazar, AR, Arreal, L, Prudkin, L, Astobiza, I, Valcarcel-Jimenez, L, Zuñiga-García, P, Fernandez-Dominguez, I, Piva, M, Caro-Maldonado, A, Sánchez-Mosquera, P, Castillo-Martín, M, Serra, V, Beraza, N, Gentilella, A, Thomas, G, Azkargorta, M, Elortza, F, Farràs, R, Olmos, D, Efeyan, A, Anguita, J, Muñoz, J, Falcón-Pérez, JM, Barrio, R, Macarulla, T, Mato, JM, Martinez-Chantar, ML, Cordon-Cardo, C, Aransay, AM, Marks, K, Baselga, J, Tabernero, J, Nuciforo, P, Manning, BD, Marjon, K & Carracedo, A 2017, 'mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer', Nature, vol. 547, no. 7661, pp. 109-113. https://doi.org/10.1038/nature22964

TY - JOUR

T1 - mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

AU - Zabala-Letona, Amaia

AU - Arruabarrena-Aristorena, Amaia

AU - Martín-Martín, Natalia

AU - Fernandez-Ruiz, Sonia

AU - Sutherland, James D

AU - Clasquin, Michelle

AU - Tomas-Cortazar, Julen

AU - Jimenez, Jose

AU - Torres, Ines

AU - Quang, Phong

AU - Ximenez-Embun, Pilar

AU - Bago, Ruzica

AU - Ugalde-Olano, Aitziber

AU - Loizaga-Iriarte, Ana

AU - Lacasa-Viscasillas, Isabel

AU - Unda, Miguel

AU - Torrano, Verónica

AU - Cabrera, Diana

AU - van Liempd, Sebastiaan M

AU - Cendon, Ylenia

AU - Polentinos-Castro, Elena

AU - Murray, Stuart

AU - Revandkar, Ajinkya

AU - Alimonti, Andrea

AU - Zhang, Yinan

AU - Barnett, Amelia

AU - Lein, Gina

AU - Pirman, David

AU - Cortazar, Ana R

AU - Arreal, Leire

AU - Prudkin, Ludmila

AU - Astobiza, Ianire

AU - Valcarcel-Jimenez, Lorea

AU - Zuñiga-García, Patricia

AU - Fernandez-Dominguez, Itziar

AU - Piva, Marco

AU - Caro-Maldonado, Alfredo

AU - Sánchez-Mosquera, Pilar

AU - Castillo-Martín, Mireia

AU - Serra, Violeta

AU - Beraza, Naiara

AU - Gentilella, Antonio

AU - Thomas, George

AU - Azkargorta, Mikel

AU - Elortza, Felix

AU - Farràs, Rosa

AU - Olmos, David

AU - Efeyan, Alejo

AU - Anguita, Juan

AU - Muñoz, Javier

AU - Falcón-Pérez, Juan M

AU - Barrio, Rosa

AU - Macarulla, Teresa

AU - Mato, Jose M

AU - Martinez-Chantar, Maria L

AU - Cordon-Cardo, Carlos

AU - Aransay, Ana M

AU - Marks, Kevin

AU - Baselga, José

AU - Tabernero, Josep

AU - Nuciforo, Paolo

AU - Manning, Brendan D

AU - Marjon, Katya

AU - Carracedo, Arkaitz

N1 - Funding: Ramón y Cajal award (to A.C., A.E., J.M., D.O.), Juan de la Cierva (to E.C., A.C.-M.), BFU grant (to R.B.: BFU2014-52282-P and BFU2011-25986), SAF grant (to A.C.: SAF2016-79381-R, FEDER/EU; M.L.M.-C.: SAF2014-54658-R; to J.M.F.-P.: SAF2015-66312; to J.M.M: SAF 2014-52097R; to A.E.: SAF2015-67538-R; to J.A.: SAF2015-65327R; to G.T.: SAF2011-24967) from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO); European Union (to A.C.: ERC-StG-336343, PoC754627; to A.C.-M.: CIG 660191; to J.A.: 602272; to A.E.: ERC-2014-STG-638891); Basque Government Department of Health (to V.T.: 2016111109; to J.M.F.-P: 2015111149), Department of Education (to A.C.: PI2012/03 and IKERTALDE I.T.1106-16; to R.B.: PI2012/42; to M.L.M.-C.: 2013) and PhD grants (to A.A.-A. and L.V.-J.); AECC (to V.T.: 2016 JP Bizkaia; to N.M.-M.: 2011 JP Bizkaia; to M.L.M.-C.); ISCIII (to A.C.: PI10/01484, PI13/00031; to J.M.: Proteored PR.B.2 and grant PT13/0001; to R.F.: PI15/209; to V.S.: PI13/01714, CP14/00228); Ramón Areces foundation (to J.M.F.-P.); Basque Department of Industry, Tourism and Trade (Etortek) (to A.C.); FERO Foundation (to A.C., V.S.); Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (to V.T.: BIO15/CA/052); BBVA Foundation (to A.C.; P.N. team); National Institutes of Health (to C.C.-C. and M.C.: P01CA087497; to J.M.M.: R01AT001576); Fundación CRIS contra el Cáncer (to D.O. team); 2014 Stewart Rahr Young Investigator Award from the Prostate Cancer Foundation (to D.O.); FPU predoctoral fellowship (to Y.C.: 15/05126); Catalan Agency AGAUR (to V.S.: 2014 SGR 1331); Medical Research Council (to R. Bago, D. Alessi laboratory: grant number MC_UU_12016/2). The activity of CIBERONC was co-funded with FEDER funds.

PY - 2017/7/6

Y1 - 2017/7/6

N2 - Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

AB - Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

KW - Journal article

U2 - 10.1038/nature22964

DO - 10.1038/nature22964

M3 - Letter

C2 - 28658205

SN - 0028-0836

VL - 547

SP - 109

EP - 113

JO - Nature

JF - Nature

IS - 7661

ER -

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Abstract

Keywords

UN SDGs

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