PTEN, a negative regulator of the phosphatidylinositol-3-kinase/AKT pathway, is an important modulator of insulin signaling. To determine the metabolic function of pancreatic Pten, we generated pancreas-specific Pten ...PTEN, a negative regulator of the phosphatidylinositol-3-kinase/AKT pathway, is an important modulator of insulin signaling. To determine the metabolic function of pancreatic Pten, we generated pancreas-specific Pten knockout （PPKO） mice. PPKO mice had enlarged pancreas and elevated proliferation of acinar cells. They also exhibited hypoglycemia, hypoinsulinemia, and altered amino metabolism. Notably, PPKO mice showed delayed onset of streptozotocin （STZ）-induced diabetes and sex-biased resistance to high-fat-diet （HFD）-induced diabetes. To investigate the mechanism for the resistance to HFD-induced hyperglycemia in PPKO mice, we evaluated AKT phosphorylation in major insulin-responsive tissues： the liver, muscle, and fat. We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver. The phosphorylation of AKT and its downstream substrate GSK3β was increased in the liver of PPKO mice, while PTEN level was decreased without detectable excision of Pten allele in the liver of PPKO mice. Proteomics analysis revealed dramatically decreased level of 78-kDa glucose-regulated protein （GRP78） in the liver of PPKO mice, which may also contribute to the lower blood glucose level of PPKO mice fed with HFD. Together, our findings reveal a novel response in the liver to pancreatic defect in metabolic regulation, adding a new dimension to understanding diabetes resistance.展开更多
The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted...The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.展开更多
基金This research was supported by grants from the Ministry of Ed- ucation （705001）, National Basic Research Program of China （973 Program 2009CB941200）, National Natural Science Foundation of China （30830061 and 30421004）, and a 111 project to H Deng. We thank Dr Tak Wah Mak （University of Alberta, Canada） for kindly providing the Ptern mice, Dr Guoqiang Gu （Vanderbilt University, USA） for kindly providing the plasmid of Pdxl-Cre, and Dr C Wright （Vanderbilt University, USA） for the PDX1 antibody. We thank the Model Animal Research Center of Nanjing University for B6 129-Gt（ROSA）26Sor tm/Sho/J mice and the Research Center for Proteome Analysis for proteomics analysis. We thank Dr Matt Stremlau, Dr Hui Zhang, Jun Cai, Han Qin, Jian Li, Yan Shi, Haisheng Zhou, and Fei Ye for their critical reading of the manu- script. We also thank Wei Jiang, Yushan Guo, Jie Yang, Chengyan Wang, Hui Zhang, and other colleagues in our laboratory for providing technical assistance and advice during the experiments.
文摘PTEN, a negative regulator of the phosphatidylinositol-3-kinase/AKT pathway, is an important modulator of insulin signaling. To determine the metabolic function of pancreatic Pten, we generated pancreas-specific Pten knockout （PPKO） mice. PPKO mice had enlarged pancreas and elevated proliferation of acinar cells. They also exhibited hypoglycemia, hypoinsulinemia, and altered amino metabolism. Notably, PPKO mice showed delayed onset of streptozotocin （STZ）-induced diabetes and sex-biased resistance to high-fat-diet （HFD）-induced diabetes. To investigate the mechanism for the resistance to HFD-induced hyperglycemia in PPKO mice, we evaluated AKT phosphorylation in major insulin-responsive tissues： the liver, muscle, and fat. We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver. The phosphorylation of AKT and its downstream substrate GSK3β was increased in the liver of PPKO mice, while PTEN level was decreased without detectable excision of Pten allele in the liver of PPKO mice. Proteomics analysis revealed dramatically decreased level of 78-kDa glucose-regulated protein （GRP78） in the liver of PPKO mice, which may also contribute to the lower blood glucose level of PPKO mice fed with HFD. Together, our findings reveal a novel response in the liver to pancreatic defect in metabolic regulation, adding a new dimension to understanding diabetes resistance.
基金The Drug Development Unit of the Royal Marsden NHS Foundation TrustThe Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K.+1 种基金Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research)the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research)
文摘The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.
