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mTORC1-mediated translational elongation limits intestinal tumour initiation and growth
William J Faller1, Thomas J Jackson2, John Rp Knight2
1Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Abstract:
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.
Insights
Loss of APC function in colorectal cancer cells unexpectedly requires mTORC1-driven translation elongation, not initiation. Rapamycin treatment halts tumor growth by targeting this pathway, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Adenomatous polyposis coli (APC) gene inactivation is a key event in colorectal cancer (CRC) development.
- The mechanistic target of rapamycin (mTOR) pathway regulates cell proliferation and tumor growth.
- Current understanding implicates mTOR in upregulating translational initiation, predicting limited efficacy of mTOR inhibitors like rapamycin in APC-deficient cancers.
Purpose of the Study:
- To investigate the role of mTOR signaling in APC-deficient colorectal cancer.
- To identify specific vulnerabilities in cancer cells lacking APC function.
- To explore therapeutic interventions targeting the mTOR pathway in colorectal cancer.
Main Methods:
- Utilized mouse models of Apc-deficient colorectal tumors.
- Analyzed protein synthesis, focusing on translational initiation and elongation.
- Investigated the mechanism of mTOR complex 1 (mTORC1) signaling in enterocyte proliferation.
- Assessed the effect of rapamycin treatment on established APC-deficient adenomas.
Main Results:
- mTORC1 activity is essential for the proliferation of Apc-deficient enterocytes, but not wild-type.
- APC-deficient cells exhibit increased protein synthesis, with translation elongation being the rate-limiting step.
- mTORC1-mediated inhibition of eukaryotic elongation factor 2 kinase (eEF2K) is crucial for APC-deficient cell proliferation.
- Rapamycin treatment induced growth arrest and differentiation in established APC-deficient tumors.
Conclusions:
- APC-deficient colorectal cancer cells have a unique dependence on mTORC1 for translation elongation.
- Inhibition of translation elongation, rather than initiation, is a critical therapeutic target.
- Clinically approved drugs like rapamycin show potential for treating APC-deficient colorectal tumors by targeting eEF2K via the mTORC1-S6K axis.
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