Targeting Protein Synthesis in Colorectal Cancer

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.

Intracellular Porphyromonas gingivalis Promotes the Proliferation of Colorectal Cancer Cells via the MAPK/ERK Signaling Pathway

“…When comparing the P. gingivalis 33277 and control groups, 51 pathways were upregulated and 44 pathways were downregulated ( Figure 4C ), and the top 20 pathways are shown in Figure 4D . Included among these pathways were proliferation related pathways, including the PI3K-Akt signaling and MAPK signaling pathways ( Fang and Richardson, 2005 ; Schmidt et al, 2020 ). Moreover, as shown in Figure 4E , we compared DEGs associated with the PI3K-Akt and MAPK signaling pathways between P. gingivalis 33277 and the control groups (the Log2 Fold Change” and “Adjusted P-Value” information are shown in Supplementary Table 2 ).…”

NCOR1 Sustains Colorectal Cancer Cell Growth and Protects against Cellular Senescence

“…We then used the IPA software to generate signaling cellular pathway analyses of the common genes influenced by NCOR1 expression in each of these cell lines. EIF2 signaling, crucial to initiate translation and upregulated in CRC [32], was predicted to be downregulated in the absence of NCOR1 in both CRC cell lines (Figure 7B). In accordance with the anti-tumorigenic role of AMP-activated kinase (AMPK) [33], this pathway was also upregulated in the absence of NCOR1 (Figure 7B).…”

“…We then used the IPA software to generate signaling cellular pathway analyses of the common genes influenced by NCOR1 expression in each of these cell lines. EIF2 signaling, crucial to initiate translation and upregulated in CRC [32], was predicted to be downregulated in the absence of…”

eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis

“…Phosphorylation of eIF2α (S51, p-eIF2α, thereafter) is the core of evolutionally conserved ‘integrated stress response’ (ISR) ( Hetz et al, 2013 ; Tabas and Ron, 2011 ; Tameire et al, 2015 ; Cubillos-Ruiz et al, 2017 ) and elevated in many cancers including CRC ( Schmidt et al, 2019 ; Schmidt et al, 2020 ). In mammals, four eIF2α kinases are activated by distinct stresses such as nutrient deficiency, misfolded proteins, viral infection, or oxidative stress, and GCN2 is activated by amino acid starvation and conserved from yeast to human ( Castilho et al, 2014 ).…”