AIM: To investigate the role of activating transcription factor 4(ATF4) in glucose deprivation(GD) induced colorectal cancer(CRC) drug resistance and the mechanism involved.METHODS: Chemosensitivity and apoptosis were...AIM: To investigate the role of activating transcription factor 4(ATF4) in glucose deprivation(GD) induced colorectal cancer(CRC) drug resistance and the mechanism involved.METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RTPCR and Western blot were used to detect the mR NA and protein expression of drug resistance gene 1(MDR1), respectively.RESULTS: GD protected CRC cells from drug-induced apoptosis(oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug resensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells. CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.展开更多
Increasing evidence indicates that Calumenin(CALU),which is localized in the endoplasmic reticulum,is significantly associated with tumor progression.However,the effect of CALU on patients with clear cell renal cell c...Increasing evidence indicates that Calumenin(CALU),which is localized in the endoplasmic reticulum,is significantly associated with tumor progression.However,the effect of CALU on patients with clear cell renal cell carcinoma(ccRCC)is unknown.By integrating multi-omics data and molecular biology experiments,we found that CALU expression was signifi-cantly increased in tumors compared with normal tissues,and the pathological grade and prognosis of patients were correlated with CALU expression.Next,knockdown or ectopic expression of CALU could affect the proliferative and invasive abilities of ccRCC cells.Moreover,immune landscape characterization revealed that CALU expression was positively associated with neutrophils and macrophages,whereas it was negatively associated with natural killer T cells and CD8^(+)T cells.Single-cell sequencing showed that the localization and binding targets of CALU mainly involved monocytes/macrophages and CD4^(+)and CD8^(+)T-cells.Sensitivity analysis of common chemotherapeutic drugs showed that high expression of CALU could sensitize chemotherapeutic drugs such as 5Z-7-Oxozeaenol,AMG-706 and Cytarabine,but could lead to drug resistance to chemotherapeutic drugs such as Embelin,Salubrinal and Tipifarnib.We demonstrated a significant correlation between high CALU expression and poor patient survival.Further,we demonstrated a correlation between CALU expression,tumor microenvironment,and the sensitivity of patients to common chemo-and immuno-therapy drugs.Thus,our results indicate that CALU could be a biomarker and designing personalized treatment approaches for ccRCC patients.展开更多
基金Supported by National Natural Science Foundation of China,No.81000867,No.81272299,No.81301784 and No.81301920Natural Science Foundation of Jiangsu Province,No.BK20150004 and No.BK20151108+3 种基金the Fundamental Research Funds for the Central Universities,No.NOJUSRP51619BMedical Key Professionals Program of Jiangsu Province,No.RC2011031"333" Talents Project of Jiangsu ProvinceHospital Management Center of Wuxi,No.YGZXM1524
文摘AIM: To investigate the role of activating transcription factor 4(ATF4) in glucose deprivation(GD) induced colorectal cancer(CRC) drug resistance and the mechanism involved.METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RTPCR and Western blot were used to detect the mR NA and protein expression of drug resistance gene 1(MDR1), respectively.RESULTS: GD protected CRC cells from drug-induced apoptosis(oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug resensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells. CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.
基金supported by grants from the National Key Research and Development Project(No.2019YFC1316005)Natural Science Foundation of China(No.82172817,82172741)+5 种基金Natural Science Foundation of Shanghai(No.20ZR1413100)Shanghai“Science and Technology Innovation Action Plan”Medical Innovation Research Project(22Y11905100)Shanghai Municipal Health Bureau Project(No.2020CXJQ03)Beijing Xisike Clinical Oncology Research Foundation(No.Y-HR2020MS-0948)Scientific Innovation Project of Shanghai Education Committee(2021-01-07-00-07-E00080)Shanghai Anti-Cancer Association Eyas Project(No.SACA-CY21A06 and No.SACA-CY21B01).
文摘Increasing evidence indicates that Calumenin(CALU),which is localized in the endoplasmic reticulum,is significantly associated with tumor progression.However,the effect of CALU on patients with clear cell renal cell carcinoma(ccRCC)is unknown.By integrating multi-omics data and molecular biology experiments,we found that CALU expression was signifi-cantly increased in tumors compared with normal tissues,and the pathological grade and prognosis of patients were correlated with CALU expression.Next,knockdown or ectopic expression of CALU could affect the proliferative and invasive abilities of ccRCC cells.Moreover,immune landscape characterization revealed that CALU expression was positively associated with neutrophils and macrophages,whereas it was negatively associated with natural killer T cells and CD8^(+)T cells.Single-cell sequencing showed that the localization and binding targets of CALU mainly involved monocytes/macrophages and CD4^(+)and CD8^(+)T-cells.Sensitivity analysis of common chemotherapeutic drugs showed that high expression of CALU could sensitize chemotherapeutic drugs such as 5Z-7-Oxozeaenol,AMG-706 and Cytarabine,but could lead to drug resistance to chemotherapeutic drugs such as Embelin,Salubrinal and Tipifarnib.We demonstrated a significant correlation between high CALU expression and poor patient survival.Further,we demonstrated a correlation between CALU expression,tumor microenvironment,and the sensitivity of patients to common chemo-and immuno-therapy drugs.Thus,our results indicate that CALU could be a biomarker and designing personalized treatment approaches for ccRCC patients.
