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Targeting Protein Synthesis in Colorectal Cancer
Stefanie Schmidt1,2, Sarah Denk1,2, Armin Wiegering1,2,3
1Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
Abstract:
Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy.
Insights
Deregulation of protein synthesis drives colorectal cancer (CRC) growth by altering mRNA translation. Targeting these translation mechanisms offers a promising therapeutic strategy for CRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Protein synthesis is vital for cell growth and survival, tightly regulated under physiological conditions.
- Deregulation of protein synthesis, particularly mRNA translation, is a hallmark of cancer, including colorectal cancer (CRC).
- Mutations in signaling pathways (WNT, RAS/MAPK, PI3K/AKT, mTOR) and altered expression of translation factors contribute to aberrant protein synthesis in CRC.
Purpose of the Study:
- To review the mechanisms underlying deregulated mRNA translation in colorectal cancer.
- To highlight recent therapeutic strategies targeting these mechanisms for CRC treatment.
Main Methods:
- Review of existing literature on molecular mechanisms of protein synthesis regulation in CRC.
- Analysis of preclinical studies investigating therapeutic interventions targeting mRNA translation in CRC models.
Main Results:
- Multiple signaling pathways and translation factors are implicated in the deregulation of mRNA translation in CRC.
- Preclinical studies show promising results for therapeutic strategies targeting translation machinery in cell lines, organoids, and mouse models.
- Despite in vitro success, clinical translation of these therapeutic strategies for CRC patients remains limited.
Conclusions:
- Aberrant mRNA translation is a critical driver in colorectal cancer development and progression.
- Targeting the translational machinery presents a potential therapeutic avenue for CRC.
- Further research and clinical trials are needed to translate promising preclinical findings into effective patient treatments.
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