Department of Zoology, Kakatiya University Warangal, Andhra Pradesh, India.
Front Oncol. 2013 Apr 12;3:85. doi: 10.3389/fonc.2013.00085. eCollection 2013.
The PI3K-Akt pathway together with one of its downstream targets, the mechanistic target of rapamycin (mTOR; also known as the mammalian target of rapamycin) is a highly deregulated pathway in cancers. mTOR exists in two complexes, mTORC1 and mTORC2. Akt phosphorylated at T308 inhibits TSC1/2 complex to activate mTORC1; mTORC2 is recognized as the kinase phosphorylating Akt at S473. Inhibition of autophagy by mTORC1 was shown to rescue disheveled (Dvl) leading to activation of Wnt pathway. Cyclin D1 and the c-Myc are activated by the Wnt signaling. Cyclin D1 is a key player in initiation of cell cycle. c-Myc triggers metabolic reprograming in G1 phase of cell cycle, which also activates the transcription factors like FoxO and p53 that play key roles in promoting the progression of cell cycle. While the role of p53 in cancer cell metabolism in arresting glycolysis and inhibition of pentose phosphate pathway has come to be recognized, there are confusions in the literature on the role of FoxO and that of rictor. FoxO was shown to be the transcription factor of rictor, in addition to the cell cycle inhibitors like p21. Rictor has dual roles; inhibition of c-Myc and constitution of mTORC2, both of which are key factors in the exit of G1-S phase and entry into G2 phase of cell cycle. A model is presented in this article, which suggests that the PI3K-Akt-mTOR and Wnt pathways converge and regulate the progression of cell cycle through G0-G1-S-phases and reprogram the metabolism in cancer cells. This model is different from the conventional method of looking at individual pathways triggering the cell cycle.
PI3K-Akt 通路及其下游靶标之一，即雷帕霉素的机制靶点（mTOR；也称为哺乳动物雷帕霉素靶标），在癌症中是高度失调的通路。mTOR 存在于两种复合物中，mTORC1 和 mTORC2。Akt 在 T308 位点磷酸化可抑制 TSC1/2 复合物从而激活 mTORC1；mTORC2 被认为是在 S473 位点磷酸化 Akt 的激酶。mTORC1 对自噬的抑制作用被证明可以挽救蓬乱蛋白（Dvl），从而激活 Wnt 通路。细胞周期蛋白 D1 和 c-Myc 被 Wnt 信号激活。细胞周期蛋白 D1 是启动细胞周期的关键因子。c-Myc 在细胞周期的 G1 期触发代谢重编程，这也激活了转录因子，如 FoxO 和 p53，它们在促进细胞周期进展中发挥关键作用。虽然 p53 在癌症细胞代谢中的作用已被认识到，即抑制糖酵解和抑制戊糖磷酸途径，但在文献中关于 FoxO 和 rictor 的作用存在混淆。FoxO 除了细胞周期抑制剂如 p21 外，还是 rictor 的转录因子。rictor 具有双重作用；抑制 c-Myc 和构成 mTORC2，这两者都是细胞周期从 G1-S 期退出并进入 G2 期的关键因素。本文提出了一个模型，该模型表明 PI3K-Akt-mTOR 和 Wnt 通路通过 G0-G1-S 期汇聚并调节细胞周期的进展，并重新编程癌细胞的代谢。这个模型与传统的方法不同，传统方法是观察单个通路触发细胞周期。
