Institute of Nutrition, Friedrich Schiller University Jena, Dornburger Str. 24, 07743 Jena, Germany.
Sci Rep. 2016 Nov 16;6:37120. doi: 10.1038/srep37120.
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.
2 型糖尿病患者癌症死亡率的增加很可能是肿瘤发展和能量代谢之间紧密联系的证据。目前研究的一个主要焦点仍然是确定这两种疾病的关键蛋白，并开发相应的抑制剂。在这项研究中，我们将两阶段 BALB/c-3T3 细胞转化测定法（BALB-CTA）与 IR/IGF-1R 抑制剂 OSI-906（linisitinib）相结合，分析了非转化和转化细胞中蛋白活性和能量参数的变化。OSI-906 成功抑制了 IR/IGF-1R 的磷酸化，并降低了非转化细胞的细胞生长。在 BALB-CTA 中，持续用 OSI-906 处理可剂量依赖性地降低细胞转化，而临时处理则表明在促进阶段具有预防作用。此外，尽管几种关键蛋白受到影响，但仍有可能表明 OSI-906 对 GSK3、Erk 1/2 和 S6 蛋白磷酸化的细胞焦点减少作用并不重要。综上所述，BALB-CTA 证实了 OSI-906 的动物研究结果，并增强了对其作用模式的认识。因此，BALB-CTA 提供了更精确分析转化过程变化的机会，并有助于确定有效的癌症治疗方法。
