Abstract
Aberrant signaling through insulin (Ins) and insulin-like growth factor I (IGF1) receptors contribute to the risk and advancement of many cancer types by activating cell survival cascades. Similarities between these pathways have thus far prevented the development of pharmacological interventions that specifically target either Ins or IGF1 signaling. To identify differences in early Ins and IGF1 signaling mechanisms, we developed a dual receptor (IGF1R & InsR) computational response model. The model suggested that ribosomal protein S6 kinase (RPS6K) plays a critical role in regulating MAPK and Akt activation levels in response to Ins and IGF1 stimulation. As predicted, perturbing RPS6K kinase activity led to an increased Akt activation with Ins stimulation compared to IGF1 stimulation. Being able to discern differential downstream signaling, we can explore improved anti-IGF1R cancer therapies by eliminating the emergence of compensation mechanisms without disrupting InsR signaling.
Highlights
Insulin and type I insulin-like growth factor (IGF1) are closely related hormones critical to development and metabolism [1,2,3,4]
Molecules that are known to bind to IGF1R bind to the closely related insulin receptor (InsR) and can disrupt metabolism in a fashion similar to diabetes
By fitting the model to data, we identify potential differences in IGF1R and InsR signaling–our model predicts that feedback from the ribosomal protein
Summary
Insulin and type I insulin-like growth factor (IGF1) are closely related hormones critical to development and metabolism [1,2,3,4]. Their receptors, InsR and IGF1R, are structurally and functionally similar, showing 60% overall amino acid sequence similarity and 84% identity at the kinase domain [5,6]. Increased insulin and IGF1 levels have been shown to correlate with an increased risk of several cancer types [7,8,9]. Insulin resistance has been associated with type II diabetes and obesity, where increased insulin levels are shown to correlate with increased risk of several cancer types [4,7,8,19]
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