近几年来,关于哺乳动物雷帕霉素靶(mammalian target of rapamycin,mTOR)在各种哺乳动物细胞中调节肌动蛋白微丝极化及肌球蛋白微丝网形成的研究一直在不断地取得新的进展。尽管到目前为止,包括mTORC2上游和下游在内的相关的调控路径还...近几年来,关于哺乳动物雷帕霉素靶(mammalian target of rapamycin,mTOR)在各种哺乳动物细胞中调节肌动蛋白微丝极化及肌球蛋白微丝网形成的研究一直在不断地取得新的进展。尽管到目前为止,包括mTORC2上游和下游在内的相关的调控路径还未明确,但是因为mTORC的生物学多样性,使其成为了当今生物学研究的焦点之一。基于长久以来特别是近五年对mTORC2的研究,在涉及细胞运动迁移、增殖分化、蛋白质合成、凋亡及自噬等生物学功能的研究中,一些重要的下游相关调控分子和蛋白相继被发现,比如P-Rex1/2、Rho家族GTPases、PKC、cAMP、p27Kip1等。该综述着重总结了mTORC2实现这些生物学功能所可能通过的四条路径。当然,仍然需要大量的实验数据和研究证据进一步地证实和完善这些已经发现的可能存在的路径。展开更多
Glioblastoma （GBM） is one of the most lethal human cancers. Genomic analyses define the molecular architecture of GBM and highlight a central function for mechanistic target of rapamycin （roTOR） signaling, roTOR k...Glioblastoma （GBM） is one of the most lethal human cancers. Genomic analyses define the molecular architecture of GBM and highlight a central function for mechanistic target of rapamycin （roTOR） signaling, roTOR kinase exists in two multi- protein complexes, namely, mTORC 1 and mTORC2. These complexes differ in terms of function, regulation and rapamycin sensitivity, mTORC 1 is well established as a cancer drug target, whereas the functions of mTORC2 in cancer, including GBM, remains poorly understood. This study reviews the recent findings that demonstrate a central function ofmTORC2 in regulating tumor growth, metabolic reprogramming, and targeted therapy resistance in GBM, which makes mTORCZ as a critical GBM drug target.展开更多
Background:Sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma(HCC).However,resistance to sorafenib...Background:Sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma(HCC).However,resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of sorafenib.As the activation of AKT/mTOR played a pivotal role in sorafenib resistance,we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC cells.Methods:The sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell lines.The synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay method.Apoptosis induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western blotting.Results:Sorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells,which underscores the significance of AKT activation.Torin2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis induction.Torin2 successfully suppressed the sorafenib-activated mTORC2-AKT axis,leading to the dephosphorylation of Ser136 in BAD protein,and increased the expression of total BAD,which contributed to the apoptosis in sorafenibresistant HCC cells.Conclusions:In this study,Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenibresistant HCC cells,via the suppression of mTORC2-AKT-BAD pathway.Our results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.展开更多
文摘近几年来,关于哺乳动物雷帕霉素靶(mammalian target of rapamycin,mTOR)在各种哺乳动物细胞中调节肌动蛋白微丝极化及肌球蛋白微丝网形成的研究一直在不断地取得新的进展。尽管到目前为止,包括mTORC2上游和下游在内的相关的调控路径还未明确,但是因为mTORC的生物学多样性,使其成为了当今生物学研究的焦点之一。基于长久以来特别是近五年对mTORC2的研究,在涉及细胞运动迁移、增殖分化、蛋白质合成、凋亡及自噬等生物学功能的研究中,一些重要的下游相关调控分子和蛋白相继被发现,比如P-Rex1/2、Rho家族GTPases、PKC、cAMP、p27Kip1等。该综述着重总结了mTORC2实现这些生物学功能所可能通过的四条路径。当然,仍然需要大量的实验数据和研究证据进一步地证实和完善这些已经发现的可能存在的路径。
基金supported by grants from the National Institute for Neurological Diseases and Stroke(NS73831)the National Cancer Institute(CA151819)+1 种基金The Ben and Catherine Ivy Foundation,the Defeat GBM Research Collaborative,a subsidiary of National Brain Tumor Societyby the generous donations from the Ziering Family Foundation in memory of Sigi Ziering
文摘Glioblastoma （GBM） is one of the most lethal human cancers. Genomic analyses define the molecular architecture of GBM and highlight a central function for mechanistic target of rapamycin （roTOR） signaling, roTOR kinase exists in two multi- protein complexes, namely, mTORC 1 and mTORC2. These complexes differ in terms of function, regulation and rapamycin sensitivity, mTORC 1 is well established as a cancer drug target, whereas the functions of mTORC2 in cancer, including GBM, remains poorly understood. This study reviews the recent findings that demonstrate a central function ofmTORC2 in regulating tumor growth, metabolic reprogramming, and targeted therapy resistance in GBM, which makes mTORCZ as a critical GBM drug target.
基金a grant from Medical and Health Science and Technology Program of Zhejiang Province(2019RC076).
文摘Background:Sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma(HCC).However,resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of sorafenib.As the activation of AKT/mTOR played a pivotal role in sorafenib resistance,we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC cells.Methods:The sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell lines.The synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay method.Apoptosis induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western blotting.Results:Sorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells,which underscores the significance of AKT activation.Torin2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis induction.Torin2 successfully suppressed the sorafenib-activated mTORC2-AKT axis,leading to the dephosphorylation of Ser136 in BAD protein,and increased the expression of total BAD,which contributed to the apoptosis in sorafenibresistant HCC cells.Conclusions:In this study,Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenibresistant HCC cells,via the suppression of mTORC2-AKT-BAD pathway.Our results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.
