Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation

Hyperactivation of phosphatidylinositol-3 kinase (PI3K) signaling is a prominent feature in cancer cells. However, the mechanism underlying malignant behaviors in the state remains unknown. Here, we describe a mechanism of cancer drug resistance through protein synthesis pathway, downstream of PI3K signaling. An optogenetic tool (named PPAP2) controlling the PI3K signaling was developed. Melanoma cells stably expressing PPAP2 (A375-PPAP2) acquired resistance to a cancer drug in the hyperactivation state. Proteome analyses revealed that expression of the antiapoptotic factor tumor necrosis factor alpha–induced protein 8 (TNFAIP8) was upregulated. The TNFAIP8 upregulation was mediated by protein translation from pre-existing mRNA. These results suggest that cancer cells escape death via upregulation of TNFAIP8 expression from pre-existing mRNA even though alkylating cancer drugs damage DNA. Comparative gene expression profiling analysis of RNA-seq data of A375-PPAP2.2 cells with or without PI3K signaling hyperactivation.