磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子...磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子,将多种生长因子及细胞因子的信号传递到细胞内,从而对细胞增殖、分化、凋亡和葡萄糖转运等多种生物过程起重要的调节作用.PTEN(phosphatase and tensin homologue)是PI3K信号通路的重要负调节因子.本文将对PI3K-Akt信号通路在糖代谢中的作用予以简要综述.展开更多
The phosphatidylinositol 3 kinase （PI3K）/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a c...The phosphatidylinositol 3 kinase （PI3K）/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma （RCC） is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarize the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway.展开更多
AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarci...AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS： The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines （RMCCA1 and KKU100） by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 （CXCL12）. RESULTS： Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 （ERK1/2） and phosphoinositide 3-kinase （PI3K） and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor （AMD3100） abrogated CXCL12-induced phosphorylation of MEKI/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor （U0126） or PI3K inhibitor （LY294002） also attenuated the effect of CXCL12- induced cholangiocarcinoma cell invasion. CONCLUSION： These results indicated that the activation of CXCR4 and its signaling pathways （MEK1/2 and Akt） are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.展开更多
文摘磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子,将多种生长因子及细胞因子的信号传递到细胞内,从而对细胞增殖、分化、凋亡和葡萄糖转运等多种生物过程起重要的调节作用.PTEN(phosphatase and tensin homologue)是PI3K信号通路的重要负调节因子.本文将对PI3K-Akt信号通路在糖代谢中的作用予以简要综述.
基金supported by the grant from The University of Texas MD Anderson Cancer Center Kidney Cancer Multidisciplinary Research Program to ZDthe NCI CCSG grant(No. P30 CA016672)the GDAC grant(No.5U24CA143883)
文摘The phosphatidylinositol 3 kinase （PI3K）/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma （RCC） is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarize the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway.
基金Supported by the Grant from National Center for Genetic Engineering and Biotechnology,Thailand and Rajavithi HospitalFund
文摘AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS： The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines （RMCCA1 and KKU100） by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 （CXCL12）. RESULTS： Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 （ERK1/2） and phosphoinositide 3-kinase （PI3K） and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor （AMD3100） abrogated CXCL12-induced phosphorylation of MEKI/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor （U0126） or PI3K inhibitor （LY294002） also attenuated the effect of CXCL12- induced cholangiocarcinoma cell invasion. CONCLUSION： These results indicated that the activation of CXCR4 and its signaling pathways （MEK1/2 and Akt） are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.
