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1.
J Cell Sci ; 134(1)2021 01 13.
Article in English | MEDLINE | ID: mdl-33441326

ABSTRACT

Cell division, differentiation and function are largely dependent on accurate proteome composition and regulated gene expression. To control this, protein synthesis is an intricate process governed by upstream signalling pathways. Eukaryotic translation is a multistep process and can be separated into four distinct phases: initiation, elongation, termination and recycling of ribosomal subunits. Translation initiation, the focus of this article, is highly regulated to control the activity and/or function of eukaryotic initiation factors (eIFs) and permit recruitment of mRNAs to the ribosomes. In this Cell Science at a Glance and accompanying poster, we outline the mechanisms by which tumour cells alter the process of translation initiation and discuss how this benefits tumour formation, proliferation and metastasis.


Subject(s)
Neoplasms , Ribosomes , Eukaryotic Initiation Factors/metabolism , Humans , Neoplasms/genetics , Neoplasms/metabolism , Peptide Chain Initiation, Translational , Protein Biosynthesis , RNA, Messenger/metabolism , Ribosomes/genetics , Ribosomes/metabolism
2.
PLoS One ; 17(2): e0262364, 2022.
Article in English | MEDLINE | ID: mdl-35130302

ABSTRACT

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells' proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells' survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.


Subject(s)
Colorectal Neoplasms
3.
Cancer Discov ; 11(5): 1228-1247, 2021 05.
Article in English | MEDLINE | ID: mdl-33328217

ABSTRACT

KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.


Subject(s)
Colorectal Neoplasms/genetics , Eukaryotic Initiation Factor-4E/drug effects , Intracellular Signaling Peptides and Proteins/drug effects , MTOR Inhibitors/pharmacology , Protein Serine-Threonine Kinases/drug effects , Animals , Colorectal Neoplasms/metabolism , Disease Models, Animal , Eukaryotic Initiation Factor-4E/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Inbred C57BL , Phosphorylation , Protein Serine-Threonine Kinases/metabolism
4.
Sci Rep ; 8(1): 12096, 2018 08 14.
Article in English | MEDLINE | ID: mdl-30108309

ABSTRACT

Tumors deficient in the urea cycle enzymes argininosuccinate synthase-1 (ASS1) and ornithine transcarbamylase (OTC) are unable to synthesize arginine and can be targeted using arginine-deprivation therapy. Here, we show that colorectal cancers (CRCs) display negligible expression of OTC and, in subset of cases, ASS1 proteins. CRC cells fail to grow in arginine-free medium and dietary arginine deprivation slows growth of cancer cells implanted into immunocompromised mice. Moreover, we report that clinically-formulated arginine-degrading enzymes are effective anticancer drugs in CRC. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine to citrulline and ammonia, affects growth of ASS1-negative cells, whereas recombinant human arginase-1 (rhArg1peg5000), which degrades arginine into urea and ornithine, is effective against a broad spectrum of OTC-negative CRC cell lines. This reflects the inability of CRC cells to recycle citrulline and ornithine into the urea cycle. Finally, we show that arginase antagonizes chemotherapeutic drugs oxaliplatin and 5-fluorouracil (5-FU), whereas ADI-PEG20 synergizes with oxaliplatin in ASS1-negative cell lines and appears to interact with 5-fluorouracil independently of ASS1 status. Overall, we conclude that CRC is amenable to arginine-deprivation therapy, but we warrant caution when combining arginine deprivation with standard chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Arginine/antagonists & inhibitors , Argininosuccinate Synthase/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arginase/pharmacology , Arginase/therapeutic use , Arginine/metabolism , Cell Line, Tumor , Colon/pathology , Colorectal Neoplasms/mortality , Drug Interactions , Drug Synergism , Feasibility Studies , Female , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Follow-Up Studies , Humans , Hydrolases/pharmacology , Hydrolases/therapeutic use , Inhibitory Concentration 50 , Kaplan-Meier Estimate , Male , Mice , Ornithine Carbamoyltransferase/metabolism , Oxaliplatin/pharmacology , Oxaliplatin/therapeutic use , Polyethylene Glycols/pharmacology , Polyethylene Glycols/therapeutic use , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Retrospective Studies , Treatment Outcome , Urea/metabolism , Xenograft Model Antitumor Assays
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