IGF-II plays a crucial role in fetal and cancer development by signaling through the IGF-I receptor. We have shown that inhibition of IGF-II by resveratrol (RSV) induced apoptosis and that proIGF-II (highly expressed in cancer) was more potent than mIGF-II in inhibiting this effect. Thus, we hypothesized that IGF-II differentially regulates the signaling cascade of the IGF-I receptor to stimulate the anti-apoptotic proteins Bcl-2 and Bcl-X(L) to prevent apoptosis. RSV treatment to breast cancer cells inhibited Bcl-2 and Bcl-X(L) expression and induced mitochondrial membrane depolarization. ProIGF-II was more potent than mIGF-II in: (1) activating the PI3/Akt pathway, (2) regulating Bcl-2 and Bcl-X(L) expression, and (3) inducing phosphorylation/nuclear translocation of Cyclic AMP-responsive element binding protein. Furthermore, IGF-II differentially regulated the intracellular translocation of Bcl-2 and Bcl-X(L), a critical process in breast cancer progression to hormone-independence. Our study provides a novel mechanism of how proIGF-II promotes progression and chemoresistance in breast cancer development.

中文翻译：

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前体 IGF-II (proIGF-II) 和成熟 IGF-II (mIGF-II) 通过不同的信号通路在乳腺癌细胞中诱导 Bcl-2 和 Bcl-X L 表达。

IGF-II 通过 IGF-I 受体发出信号，在胎儿和癌症的发展中起着至关重要的作用。我们已经表明，白藜芦醇 (RSV) 对 IGF-II 的抑制诱导了细胞凋亡，并且 proIGF-II（在癌症中高度表达）在抑制这种作用方面比 mIGF-II 更有效。因此，我们假设 IGF-II 差异调节 IGF-I 受体的信号级联反应以刺激抗凋亡蛋白 Bcl-2 和 Bcl-X(L) 以防止细胞凋亡。RSV 对乳腺癌细胞的治疗抑制 Bcl-2 和 Bcl-X(L) 表达并诱导线粒体膜去极化。ProIGF-II 在以下方面比 mIGF-II 更有效：(1) 激活 PI3/Akt 通路，(2) 调节 Bcl-2 和 Bcl-X(L) 表达，以及 (3) 诱导环 AMP 的磷酸化/核易位-响应元件结合蛋白。此外，IGF-II 差异调节 Bcl-2 和 Bcl-X(L) 的细胞内易位，这是乳腺癌进展为激素非依赖性的关键过程。我们的研究提供了 proIGF-II 如何促进乳腺癌发展过程中的进展和化学抗性的新机制。