Maintenance of p-eIF2 alpha levels by the eIF2B complex is vital for colorectal cancer

Protein synthesis is an essential cellular process highly deregulated in multiple tumour types, where control of several translation factors is hijacked to benefit oncogenic growth. Here we show that colorectal cancer (CRC) is characterized specifically by elevated levels of phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2alpha). In contrast to its canonical association with reduced translation rates, we reveal that CRC with high p-eIF2alpha has increased protein synthesis rates. Thus, we hypothesize that eIF2B, the sensor of p-eIF2 alpha, plays a central role in cells’ inability to relay this inhibitory signal. Using a combination of in cellulo biochemistry, phenotypic assays, and analysis of translation upon modulation of eIF2B subunits alpha and delta, the two eIF2B subunits responsible for sensing p-eIF2 alpha, we demonstrate that CRC cells require an intact eIF2B complex to sense p-eIF2 alpha. Crucially, we show that the alpha subunit of eIF2B is necessary to translate the oncogenic programs driven by APC loss, highlighting its central role in oncogenic transformation. To conclude, we demonstrate that whilst normal cells do not depend on eIF2B alpha, CRC cells require this eIF2B subunit for correct sensing of p-eIF2 alpha and regulation of their proteostasis, thus validating eIF2B alpha as a target for therapeutic intervention in CRC.