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

Abstract 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. Significance statement Animal species differ greatly in their cancer susceptibility. Cancer rates in the mouse range from 50-90%, while two other rodent species, the naked mole rat and the blind mole rat have only a few cancer cases ever reported. Here we examined the mechanisms responsible these differences by comparing changes in transcription patters in response to oncoproteins in the mouse, naked mole rat, blind mole rat and human cells. The most striking finding was that the naked mole rat cells were resistant to transcriptional changes induced by oncogenic Ras. We found that pathways downstream of Ras were naturally attenuated in the naked mole rat. This finding identifies a novel mechanism that evolved to provide tumor resistance to the naked mole rat.