Proline Starvation Induces Unresolved ER Stress and Hinders mTORC1-Dependent Tumorigenesis.
The role of essential amino acids in metabolic reprogramming of cancer cells is now well established, whereas the role of non-essential amino acids (NEAAs) in malignancy remains less clear. Here, we have identified an important role for the NEAA proline in the tumorigenic potential of a subset of cancer cells. By profiling a large panel of cancer cell lines, we observed that proline consumption and expression of proline biosynthesis enzymes were well correlated with clonogenic and tumorigenic potential. Moreover, proline starvation or inhibition of proline biosynthesis enzymes impaired clonogenic/tumorigenic potential. Cancer cells exhibiting dependency on exogenous proline displayed hyperactivation of the mTORC1-mediated 4EBP1 signaling axis, as well as unresolved ER stress. Exogenous proline alleviated ER stress and promoted cellular homeostasis and clonogenicity. Increased dependence on proline may therefore define a specific vulnerability in some cancers that can be exploited by proline depletion.
Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Nisebita
N
Sahu
Department of Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Darlene
D
Dela Cruz
Department of Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Min
M
Gao
Department of Protein Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Wendy
W
Sandoval
Department of Bioinformatics and Computational Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Peter M
PM
Haverty
Department of Bioinformatics and Computational Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Jinfeng
J
Liu
Department of Protein Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Jean-Philippe
JP
Stephan
Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Benjamin
B
Haley
Department of Cancer Targets, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Marie
M
Classon
Department of Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Georgia
G
Hatzivassiliou
Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: settleman@calicolabs.com.
Jeff
J
Settleman
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D002999:Clone Cells; D059865:Endoplasmic Reticulum Stress; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011392:Proline / Q000096:biosynthesis / Q000172:deficiency*; D014176:Protein Biosynthesis; D012315:RNA Caps / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D046912:Multiprotein Complexes; D010750:Phosphoproteins; D012315:RNA Caps; D011392:Proline; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases