TY - JOUR
T1 - Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells
AU - Linder, Samantha J.
AU - Bernasocchi, Tiziano
AU - Martínez-Pastor, Bárbara
AU - Sullivan, Kelly D.
AU - Galbraith, Matthew D.
AU - Lewis, Caroline A.
AU - Ferrer, Christina M.
AU - Boon, Ruben
AU - Silveira, Giorgia G.
AU - Cho, Hyo Min
AU - Vidoudez, Charles
AU - Shroff, Stuti
AU - Oliveira-Costa, Joao P.
AU - Ross, Kenneth N.
AU - Massri, Rami
AU - Matoba, Yusuke
AU - Kim, Eugene
AU - Rueda, Bo R.
AU - Stott, Shannon L.
AU - Gottlieb, Eyal
AU - Espinosa, Joaquin M.
AU - Mostoslavsky, Raul
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.
AB - Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.
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U2 - 10.1038/s42255-023-00919-3
DO - 10.1038/s42255-023-00919-3
M3 - Article
C2 - 37957387
AN - SCOPUS:85176602489
SN - 2522-5812
VL - 5
SP - 2131
EP - 2147
JO - Nature Metabolism
JF - Nature Metabolism
IS - 12
ER -