AKT Promotes rRNA Synthesis and Cooperates with c-MYC to Stimulate Ribosome Biogenesis in Cancer

In addition to promoting translation, AKT also stimulates protein synthesis and cell growth by enhancing ribosome biogenesis. Building the Building Blocks Ribosomes translate mRNA into protein, and the activity of signaling pathways that promote ribosome formation (or biogenesis) is often increased in cancer cells, which have high rates of protein synthesis and cell growth. Thus, each step of ribosome biogenesis can limit cell growth, including the synthesis of ribosomal RNA (rRNA), which encodes the RNA components of the ribosome. Chan et al. found that the kinase AKT, which is frequently activated in cancer cells and was previously implicated in promoting protein translation, also promotes rRNA synthesis. Cells with increased AKT activity showed increased rRNA abundance and more ribosomes. The transcription factor c-MYC is required for ribosome biogenesis, and the gene encoding c-MYC is frequently mutated in tumors. The ability of c-MYC to promote ribosome biogenesis and cell growth in a mouse model of lymphoma was attenuated by an AKT inhibitor. These results suggest that reducing ribosome biogenesis may in part underlie the therapeutic efficacy of anticancer drugs that target AKT signaling. Precise regulation of ribosome biogenesis is fundamental to maintain normal cell growth and proliferation, and accelerated ribosome biogenesis is associated with malignant transformation. Here, we show that the kinase AKT regulates ribosome biogenesis at multiple levels to promote ribosomal RNA (rRNA) synthesis. Transcription elongation by RNA polymerase I, which synthesizes rRNA, required continuous AKT-dependent signaling, an effect independent of AKT’s role in activating the translation-promoting complex mTORC1 (mammalian target of rapamycin complex 1). Sustained inhibition of AKT and mTORC1 cooperated to reduce rRNA synthesis and ribosome biogenesis by additionally limiting RNA polymerase I loading and pre-rRNA processing. In the absence of growth factors, constitutively active AKT increased synthesis of rRNA, ribosome biogenesis, and cell growth. Furthermore, AKT cooperated with the transcription factor c-MYC to synergistically activate rRNA synthesis and ribosome biogenesis, defining a network involving AKT, mTORC1, and c-MYC as a master controller of cell growth. Maximal activation of c-MYC–dependent rRNA synthesis in lymphoma cells required AKT activity. Moreover, inhibition of AKT-dependent rRNA transcription was associated with increased lymphoma cell death by apoptosis. These data indicate that decreased ribosome biogenesis is likely to be a fundamental component of the therapeutic response to AKT inhibitors in cancer.