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Dampened PI3K/AKT signaling contributes to cancer resistance of the naked mole rat

By Jing Zhao, Xiao Tian, Yabing Zhu, Zhihui Zhang, Elena Rydkina, Yongxuan Yuan, Hongyun Zhang, Bhaskar Roy, Adam Cornwell, Eviatar Nevo, Xiaoxiao Shang, Runyue Huang, Karsten Kristiansen, Andrei Seluanov, Xiaodong Fang, Vera Gorbunova

Posted 28 Feb 2020
bioRxiv DOI: 10.1101/2020.02.27.967729

Mammalian species have a dramatically different susceptibility to cancer. However, how cancer-resistant species resist oncogenic transformation is not fully understood. Here, we performed a comprehensive analysis of oncogene-induced transcriptional changes in the fibroblasts of a cancer-prone species, the mouse, and three cancer-resistant species, the human, the blind mole rat, and the naked mole rat. We report that multiple cellular processes are more refractory to oncogene-induced transcriptional changes in blind mole-rat, naked mole-rat, or human cells compared to mouse cells, such as cell division, cell adhesion, extracellular matrix organization, and metabolism. Strikingly, naked mole rat cells are more resistant to Ras-induced transcriptional changes compared to the other three species. As a mechanism, we found that critical genes in the PI3K pathway including Akt1 and Pik3ca are downregulated in naked mole rat cells. Activating the PI3K/AKT pathway in the naked mole rat cells renders them susceptible to tumorigenic transformation. This study provides multiple new insights into anti-cancer mechanisms in cancer-resistant species of mammals.

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