Date

2023-1-9

Author

Oral, Göksu

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Limited nutrient availability in the tumor microenvironment can cause metabolic rewiring of cancer cells, resulting in the activation of various stress response pathways such as autophagy for survival. Our study showed for the first time that incubation of LoVo cells with a nutrient restriction medium containing low glucose, glutamine, and serum for 48 h resulted in the concurrent activation of two antagonistic proteins: the AMP Kinase pathway (AMPK) which is phosphorylated in response to low energy and activates catabolism and Ribosomal protein S6 (RPS6), which is activated in response to anabolic signaling, leading to protein synthesis and cell growth. The activation of AMPK was attributed to the low energy generation in the nutrient-restricted cells, leading to the induction of autophagy, as expected. The surprising observation of phosphorylation of RPS6 in the nutrientrestricted cells was attributed to the partial activation of mTORC1 and a robust activation of the MAPK pathway. The latter pathway could also be implicated in the high cell viability observed even after prolonged starvation since treatment of starved cells with a MAPK inhibitor led to a remarkable increase in cell death. Analysis of publicly available reverse phase protein array (RPPA) data from colorectal tumors with high phosphorylation of both RPS6 and AMPK revealed enrichment of oncogenic growth and transcription factors. Overall, our data suggest that low availability of nutrients may lead to the co-activation of AMPK and RPS6 as a survival mechanism in colorectal cancer cells.

Subject Keywords

Colorectal cancer, Nutrient restriction, Autophagy, mTOR pathway, MAPK pathway

URI

https://hdl.handle.net/11511/101975

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Graduate School of Natural and Applied Sciences, Thesis