mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.
Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
William J
WJ
Faller
Medical Research Council Toxicology Unit; Leicester, LE1 9HN, UK.
Thomas J
TJ
Jackson
Medical Research Council Toxicology Unit; Leicester, LE1 9HN, UK.
John Rp
JR
Knight
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Rachel A
RA
Ridgway
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Thomas
T
Jamieson
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Saadia A
SA
Karim
Medical Research Council Toxicology Unit; Leicester, LE1 9HN, UK.
Carolyn
C
Jones
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Sorina
S
Radulescu
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
David J
DJ
Huels
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Kevin B
KB
Myant
Medical Research Council Toxicology Unit; Leicester, LE1 9HN, UK.
Kate M
KM
Dudek
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Helen A
HA
Casey
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Alessandro
A
Scopelliti
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Julia B
JB
Cordero
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Marcos
M
Vidal
Inserm U845, Université Paris Descartes, Necker Medical School, 75015 Paris, France.
Mario
M
Pende
Robert Wood Johnson Medical School, Department of Pharmacology, Piscataway, New Jersey, USA.
Alexey G
AG
Ryazanov
Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
Nahum
N
Sonenberg
Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Oded
O
Meyuhas
Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Michael N
MN
Hall
Medical Research Council Toxicology Unit; Leicester, LE1 9HN, UK.
Martin
M
Bushell
Medical Research Council Toxicology Unit; Leicester, LE1 9HN, UK.
Anne E
AE
Willis
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Owen J
OJ
Sansom
D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D054736:Elongation Factor 2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D016274:Oncogene Protein p55(v-myc) / Q000378:metabolism; D010441:Peptide Chain Elongation, Translational; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D046912:Multiprotein Complexes; D016274:Oncogene Protein p55(v-myc); D020652:Peptide Elongation Factor 2; D051153:Wnt Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D054736:Elongation Factor 2 Kinase