The nucleolus is a subnuclear domain that is the hub of ribosome biogenesis and also a critical regulator of cell homeostasis. Rapid growth and division of cells in tumors is correlated with intensive nucleolar metabolism. Recently several members of the Epidermal Growth Factor Receptor family (EGFR), overexpressed at the cell surface of many cancers cells have been identified in the nucleus and nucleolus of tumor cells. Their function in this compartments remains unexplored. We focused our research on the nucleolar function of the ErbB3 receptor in glioma, a tumor without effective therapies at present. Proliferative stimuli of glioma cells through the activation of the ErbB3, via its ligand (NRG1) induces a rapid shuttling of an ErbB3 variant from the nucleolus to the cytoplasm and increases pre-rRNA synthesis. ErbB3 silencing or nucleolar stress induced by actinomycin D, reduce cell proliferation affecting cell cycle progression. Intranuclear ErbB3 localization is characterised by specific interactions with nucleolin (C23) and Upstream Binding Factor (UBF), both proteins already described as having a crucial role on ribosome biogenesis and cell cycle control. Further immunohistochemistry analysis on tissues of patients affected by glioma shows high levels of ErbB3 expression with a prevalent cytoplasmic accumulation suggesting that a nucleolar-cytoplasm ErbB3 traffic occurs in vivo. Our data point to the existence of a non canonical pathway that glioma cells use to control cell proliferation. Our results highlights the potential role of nucleolar ErbB3 receptor, as new target in glioma and the interaction between the variant ErbB3 and C23 a new field of investigation in cancer. In glioma C23 expression increases with the tumor grade and shows a shuttling from the nucleus to the cytoplasm. We hypothesed that both ErbB3 and C23 could be functionally linked and represent a new target in glioma therapy.
Numerous evidences collected over decades has demonstrated that the abnormalities in the morphology and numbers of nucleoli are the direct consequence of the over-activation of ribosome biogenesis in cancer. Recently, therapeutic approaches targeting the nucleolus in tumor have started to be considered as an emerging hallmark of cancer and several therapeutic interventions have been developed. Indeed, many cancer therapeutic drugs (actinomycin D, platinum compounds, etc.) have been proposed to elicit their anti-tumour activity via inhibiting ribosome biogenesis. A powerful novel anti-cancer agent in heamatological and prostate cancers is CX-5461. Indeed, it is the first specific inhibitor of Pol I transcription to enter the clinic, having progressed into phase I/II clinical trials in patients with advanced haematological malignancies and breast cancer. CX-5461 inhibits Pol I transcription by preventing SL-1 from interacting with the rDNA promoter resulting inhibition of Pol I activity. It induces anti-proliferative responses including cell-cycle arrest and deregulation of ribosome biogenesis.