Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1...Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.展开更多
In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS...In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.展开更多
基金This work was supported by USA National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)R01 DK093807.
文摘Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.
文摘In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.
