The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.
Both in situ and allograft models of cancer in juvenile and adult Drosophila melanogaster fruit flies offer a powerful means for unravelling cancer gene networks and cancer–host interactions. They can also be used as tools for cost-effective drug discovery and repurposing. Moreover, in situ modeling of emerging tumors makes it possible to address cancer initiating events—a black box in cancer research, tackle the innate antitumor immune responses to incipient preneoplastic cells and recurrent growing tumors, and decipher the initiation and evolution of inflammation. These studies in Drosophila melanogaster can serve as a blueprint for studies in more complex organisms and help in the design of mechanism-based therapies for the individualized treatment of cancer diseases in humans. This review focuses on new discoveries in Drosophila related to the diverse innate immune responses to cancer-related inflammation and the systemic effects that are so detrimental to the host.
Children and other vertebrate animals stunted due to malnutrition can compensate for this deficit by resuming growth at a higher-than-normal rate via a still ill-defined mechanism. High mortality and adverse effects later in life may offset the positive effects of catch-up growth. Here we report that the invertebrate Drosophila melanogaster also experiences catch-up growth following a period of starvation, and the relaxin receptor Lgr4 instigates this catch-up growth. Starved larvae compensate for weight loss by growing two or more times faster and starting maturation within the same time as the non-starved sibling by preventing a rise in insulin-like growth (IGF)-induced ecdysone under Lgr4 control. Our data reveal that catch-up growth is associated with a surge of insulin, not IGF, which may clarify how catch-up growth often leads to metabolic problems and obesity.
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