Abstract
The increased cancer mortality of diabetes type 2 patients is most likely an evidence of the tight connection between tumor development and energy metabolism. A major focus of today’s research is still the identification of key proteins of both diseases and the development of corresponding inhibitors. In this study we combined the two-stage BALB/c-3T3 cell transformation assay (BALB-CTA) with the IR/IGF-1R inhibitor OSI-906 (linsitinib) and analyzed alterations in protein activity and energy parameters in non-transformed as well as transformed cells. OSI-906 successfully inhibited the phosphorylation of IR/IGF-1R and decreased cell growth in non-transformed cells. In the BALB-CTA, a permanent treatment with OSI-906 reduced cellular transformation dose-dependently, whereas a temporary treatment gave evidence for a preventive effect in the promotion phase. Furthermore, even though several key proteins were affected, it was possible to show that the phosphorylation of GSK3, Erk 1/2 and the S6 protein are not crucial for the cell foci reducing effect of OSI-906. Taken together, the BALB-CTA confirmed results of OSI-906 from animal studies and enhanced the knowledge of its mode of action. Therefore, the BALB-CTA offers the opportunity to analyze alterations in the transformation process more precisely and will be helpful to identify effective cancer treatments.
Highlights
Reprogramming of energy metabolism was first observed by Otto Warburg, who showed that neoplastic cells favor glycolysis even in the presence of oxygen[12,13]
Evidence for the link between energy metabolism and cancer development can be found in epidemiological studies, which reveal an association between type 2 diabetes mellitus (T2D) and an increased risk for several cancer types[17,18]
The metabolic effects of insulin and IGF-1 are mediated by their corresponding receptors, the insulin receptor (IR) and the insulin-like growth factor 1 receptor (IGF-1R)
Summary
Binding of the corresponding ligands to IR, IGF-1R or hybrid receptors stimulate downstream pathways like PI3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and Ras/MEK/extracellular signal-regulated kinase (Ras/MEK/Erk), which influence cellular growth, apoptosis, proliferation, cell transformation and metastasis[29,30,31]. Modulation of IR and IGF-1 R signaling and the downstream target Akt is linked to the regulation of glucose metabolism (glucose transporter activation, stimulation of hexokinase and phosphofructokinase activity)[40,41] and OSI-906 treatment of mice has been shown to decrease glucose uptake dose-dependently[42]. As part of the chief mechanisms for controlling cell survival, differentiation, proliferation and metabolism we wanted to elucidate the roles of Akt and the protein Erk in cellular transformation[43]. To analyze the potential connection between energy metabolism and cancer mechanisms with OSI-906, we studied the role of the glycogen synthase kinase 3 (GSK3) and further parameters
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
