Besin Yoksunluğu Koşullarında Kolorektal Hücre Hatlarında Translasyonel Düzenlemenin Aydınlatılması

Tumor cells may vary in their metabolism due to changes in the availability of nutrients. The survival of cancer cells in these conditions requires them to modify signaling pathways. Protein translation is one of the pathways that is likely to be affected significantly with low nutrient availability, as the process is highly energy-intensive. Here, we examined the cellular and molecular mechanisms of how colorectal cancer cells respond to nutrient shortages within the context of protein translation. We evaluated different colorectal cancer cell lines and observed that nutrient deprivation universally limited cell division; however, the surviving cells were highly viable. We focused the study on LoVo and HCT-116 cells as both cell lines showed the activation of nutrient-sensing pathways, such as activation of AMP Kinase and inhibition of mTOR, within 2h of nutrient depletion. However, these cell lines also displayed continued activation of Ribosomal Protein S6 (RPS6), a key protein in the small ribosomal subunit and a target of mTOR in the nutrient-depleted cells. Pharmacological inhibition experiments showed that the MAPK pathway played a critical role in RPS6 phosphorylation when the cells experienced nutrient scarcity. Although global protein synthesis showed a decrease with nutrient depletion, specific proteins continued to be translated to ensure cell survival. One of the mechanisms was the activation of the Integrated Stress Response (ISR) protein ATF4, which is known to transcriptionally activate stress response genes. Overall, our data suggests that colorectal cancer cells survive under limited nutrients by ensuring the synthesis of key proteins via the MAPK and ATF4 signaling pathways.