Editors' ChoiceCancer

Fueling Cancer Growth

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Sci. Signal.  13 Aug 2013:
Vol. 6, Issue 288, pp. ec188
DOI: 10.1126/scisignal.2004619

Insulin promotes cell proliferation by activating the phosphatidylinositol 3-kinase (PI3K) pathway, which ultimately enables cellular glucose uptake. In diabetes, insulin concentrations are increased and tissues become insulin resistant. Metabolic diseases such as diabetes are associated with an increased incidence of certain cancers. Hirabayashi et al. investigated how cancer cells overcome insulin resistance, using Drosophila expressing oncogenic ras1G12V and a null allele of the Src inhibitor Csk in the eye to mimic the increased activity of Ras and Src seen in several human cancers. ras1G12V;csk–/– larvae fed high dietary sucrose (HDS), but not a calorie-matched high-fat diet, developed overgrowth in the eye field and generally died before pupariation. Decreasing the activity of the PI3K pathway in ras1G12V;csk–/– larvae reduced overgrowth. Conversely, eye tissue from ras1G12V;csk–/– larvae fed HDS showed increased PI3K activity and remained sensitive to insulin compared with that from larvae on a normal diet. Cells from ras1G12V;csk–/– larvae on a control diet had active Dronc, an initiator caspase, and were undergoing apoptosis. Although cells from ras1G12V;csk–/– larvae fed HDS had active Dronc, they also had increased abundance of Diap1, an inhibitor of caspases downstream of Dronc, and thus were not undergoing apoptosis. Such cells have been called “undead.” Increasing the activity of the insulin receptor enhanced Diap1 abundance in ras1G12V;csk–/– larvae on a control diet, whereas decreasing the activity of the PI3K pathway prevented the increase in Diap1 abundance in ras1G12V;csk–/– larvae fed HDS. Undead cells produce greater amounts of the mitogen Wingless (Wg), a phenomenon that requires the activity of the Jnk pathway. ras1G12V;csk–/–animals fed HDS showed increased Wg abundance in the eye disc, a response that was ablated by decreasing PI3K pathway activity. RNA interference (RNAi) directed against Wg in ras1G12V;csk–/–animals fed HDS reduced tumor growth and increased survival to pupariation. Decreasing JNK pathway activity reduced Wg abundance both in ras1G12V;csk–/–animals fed HDS and in ras1G12V;csk–/–animals with a constitutively active form of the insulin receptor on a control diet. The expression of the gene encoding the insulin receptor was increased in eye tissue from ras1G12V;csk–/–animals fed HDS, which was ablated by decreasing the transcriptional activity of the Wg pathway. In ras1G12V;csk–/–animals fed HDS, tumor growth was decreased and survival was increased by treatment with the type 2 diabetic drug acarbose, the canonical Wnt-signaling pathway inhibitor pyrvinium, or AD81, a polypharmacological agent that simultaneously targets the Ras, Src, and Tor pathways. Combination of acarbose, pyrvinium, and AD81 restored the survival rate of ras1G12V;csk–/–animals fed HDS to nearly that of control animals. Thus, tumors in insulin-resistant organisms may maintain insulin sensitivity through a feed-forward mechanism that requires Wnt activation of the gene encoding the insulin receptor.

S. Hirabayashi, T. J. Baranski, R. L. Cagan, Transformed Drosophila cells evade diet-mediated insulin resistance through Wingless signaling. Cell 154, 664–675 (2013). [PubMed]