Introduction:Oncogenic aaivation of the K-ras gene occurs in >90%of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy.Increase of reactive oxygen species(ROS) has also bee...Introduction:Oncogenic aaivation of the K-ras gene occurs in >90%of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy.Increase of reactive oxygen species(ROS) has also been observed in a wide spectrum of cancers.This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.Methods:ROS level,NADPH oxidase(NOX) aaivity and expression,and cell invasion were examined in human pancreatic dua epithelial E6E7 cells transfeaed with K-ras^(G12V) compared with parental E6E7 cells.The cytotoxic effea and antitumor effect of capsaicin,a NOX inhibitor,were also tested in vitro and in vivo.Results:K-ras transfeaion caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase(PI3K) pathway.Importantly,capsaicin preferentially inhibited the enzyme aaivity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells.Furthermore,capsaicin effeaively inhibited cell proliferation,prevented invasiveness of /(-ras-transformed pancreatic cancer cells,and caused minimum toxicity to parental E6E7 cells.In vivo,capsaicin exhibited antitumor aaivity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.Conclusions:K-ras oncogenic signaling causes increased ROS stress through NOX,and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors.Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.展开更多
Lung cancer is one of the most common malignant tumors with the fastest increase in the incidence rate and mortality.Even after maximum tumor resection assistance with a radiotherapy and chemotherapy combination,the r...Lung cancer is one of the most common malignant tumors with the fastest increase in the incidence rate and mortality.Even after maximum tumor resection assistance with a radiotherapy and chemotherapy combination,the recurrence of non-small cell lung cancer is still inevitable.In addition,low targeting efficiency and poor permeability of drug delivery systems strongly affect the therapeutic efficiency of anti-cancer drugs on non-small cell lung cancer.Here we designed a gemcitabine(GEM)loaded arginineglycine-aspartic acid-cysteine(RGDc)-modified gold mineralization“hybrid nanozyme bomb”(RGTG)to overcome those obstacles.RGDc modification improved the active targeting of liposomes to the tumor tissues with the second near-infrared(NIR-Ⅱ)-triggered gold-shell disruption and GEM release.The collapsed gold-shell particles with a smaller size could penetrate the tumor solid barrier and act as photothermal therapy(PTT)agents to improve PTT therapy and starvation therapy via generating gluconic acid and reactive oxygen species(ROS).Moreover,the resting reversal effect of gold particles on tumor fibroblasts can achieve accelerating tumor penetration of gold particles and GEM.Compared to monotherapy,RGTG showed significant improvement in tumor inhibition,with a tumor volume reduction of 83%compared to the control group,which provides a promising tumor treatment platform for non-small cell lung cancer(NSCLC).展开更多
Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kina...Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kinase inhibitors,such as sorafenib,are limited due to the emergence of drug resistance.While investigations have been con-ducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor,a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created.This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor.Methods:We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations,namely the murine BaF3/ITD-R and the human MV4-11-R cell lines.We performed a global untargeted metabolomics and stable isotope-labe-ling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance.Results:The resistant cells displayed fundamentally rewired metabolic profiles,characterized by a higher demand for glucose,accompanied by a reduction in glucose flux into the pentose phosphate pathway(PPP);and by an increase in oxidative stress,accompanied by an enhanced glutathione synthesis.We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation.A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells.Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency(G6PD)in the oxidative arm and transketolase(TKT)in the non-oxidative arm.In addition,we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leu-kemia cells,which was accompanied by decreased cell proliferation and an enhanced antioxidant response.Conclusions:Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.展开更多
Dear Editor,Oncogenic K-ras mutation plays a major role in malignant transformation and induces significant alterations in cancer cell metabolism[1–4].However,the major molecular players mediating metabolic alteratio...Dear Editor,Oncogenic K-ras mutation plays a major role in malignant transformation and induces significant alterations in cancer cell metabolism[1–4].However,the major molecular players mediating metabolic alterations during K-ras-driven cancer development remain elusive.The observations that tumorigenesis often requires multiple hits suggest that K-ras mutation likely needs the coordination of other molecular events that enable adaptive cellular metabolism for a full malignant transformation.Based on our previous study on the impact of K-ras onmitochondrial metabolism[1,5]and our recent findings that mitochondrial isocitrate dehydrogenase 2(IDH2)could promote the“reverse”flow of the tricarboxylic acid(TCA)cycle fromα-KG to isocitrate and enhance the survival and proliferation of acute myeloid leukemia cells[6],we investigated the potential role of IDH2 in metabolic adaptation during K-ras-driven tumorigenesis.展开更多
基金supported by research grants from the National Natural Science Foundation of China(No.81101520)the National Basic Research Program of China(973 program)(No.2013CB910304 and 2012CB967004)
文摘Introduction:Oncogenic aaivation of the K-ras gene occurs in >90%of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy.Increase of reactive oxygen species(ROS) has also been observed in a wide spectrum of cancers.This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.Methods:ROS level,NADPH oxidase(NOX) aaivity and expression,and cell invasion were examined in human pancreatic dua epithelial E6E7 cells transfeaed with K-ras^(G12V) compared with parental E6E7 cells.The cytotoxic effea and antitumor effect of capsaicin,a NOX inhibitor,were also tested in vitro and in vivo.Results:K-ras transfeaion caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase(PI3K) pathway.Importantly,capsaicin preferentially inhibited the enzyme aaivity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells.Furthermore,capsaicin effeaively inhibited cell proliferation,prevented invasiveness of /(-ras-transformed pancreatic cancer cells,and caused minimum toxicity to parental E6E7 cells.In vivo,capsaicin exhibited antitumor aaivity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.Conclusions:K-ras oncogenic signaling causes increased ROS stress through NOX,and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors.Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.
基金supported by the National Natural Science Foundation of China(No.81972892)。
文摘Lung cancer is one of the most common malignant tumors with the fastest increase in the incidence rate and mortality.Even after maximum tumor resection assistance with a radiotherapy and chemotherapy combination,the recurrence of non-small cell lung cancer is still inevitable.In addition,low targeting efficiency and poor permeability of drug delivery systems strongly affect the therapeutic efficiency of anti-cancer drugs on non-small cell lung cancer.Here we designed a gemcitabine(GEM)loaded arginineglycine-aspartic acid-cysteine(RGDc)-modified gold mineralization“hybrid nanozyme bomb”(RGTG)to overcome those obstacles.RGDc modification improved the active targeting of liposomes to the tumor tissues with the second near-infrared(NIR-Ⅱ)-triggered gold-shell disruption and GEM release.The collapsed gold-shell particles with a smaller size could penetrate the tumor solid barrier and act as photothermal therapy(PTT)agents to improve PTT therapy and starvation therapy via generating gluconic acid and reactive oxygen species(ROS).Moreover,the resting reversal effect of gold particles on tumor fibroblasts can achieve accelerating tumor penetration of gold particles and GEM.Compared to monotherapy,RGTG showed significant improvement in tumor inhibition,with a tumor volume reduction of 83%compared to the control group,which provides a promising tumor treatment platform for non-small cell lung cancer(NSCLC).
基金This study was supported by the research grant from National Key R&D Program of China(2018YFC0910203)
文摘Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kinase inhibitors,such as sorafenib,are limited due to the emergence of drug resistance.While investigations have been con-ducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor,a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created.This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor.Methods:We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations,namely the murine BaF3/ITD-R and the human MV4-11-R cell lines.We performed a global untargeted metabolomics and stable isotope-labe-ling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance.Results:The resistant cells displayed fundamentally rewired metabolic profiles,characterized by a higher demand for glucose,accompanied by a reduction in glucose flux into the pentose phosphate pathway(PPP);and by an increase in oxidative stress,accompanied by an enhanced glutathione synthesis.We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation.A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells.Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency(G6PD)in the oxidative arm and transketolase(TKT)in the non-oxidative arm.In addition,we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leu-kemia cells,which was accompanied by decreased cell proliferation and an enhanced antioxidant response.Conclusions:Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.
基金We thank the grant support from the National Key R&D Program of China(2020YFA0803300).
文摘Dear Editor,Oncogenic K-ras mutation plays a major role in malignant transformation and induces significant alterations in cancer cell metabolism[1–4].However,the major molecular players mediating metabolic alterations during K-ras-driven cancer development remain elusive.The observations that tumorigenesis often requires multiple hits suggest that K-ras mutation likely needs the coordination of other molecular events that enable adaptive cellular metabolism for a full malignant transformation.Based on our previous study on the impact of K-ras onmitochondrial metabolism[1,5]and our recent findings that mitochondrial isocitrate dehydrogenase 2(IDH2)could promote the“reverse”flow of the tricarboxylic acid(TCA)cycle fromα-KG to isocitrate and enhance the survival and proliferation of acute myeloid leukemia cells[6],we investigated the potential role of IDH2 in metabolic adaptation during K-ras-driven tumorigenesis.
