Background:Limited by difficulties in early detection and availabilities of effective treatments,pancreatic cancer is a highly malignant disease with poor prognosis.Nuclear receptors are a family of ligand‐dependent ...Background:Limited by difficulties in early detection and availabilities of effective treatments,pancreatic cancer is a highly malignant disease with poor prognosis.Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development,including cancer.In this study,we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor(LXR)agonist GW3965 in pancreatic cancer.Methods:Soft‐agar colony formation assay,xenograft tumors,Oligonucleotide microarray,Reverse transcription real‐time polymerase chain reaction,Western immunoblotting and Immunohistochemistry were used in this study.Results:We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability,inhibition of cell proliferation,stimulation of cell death,and suppression of colony formation,which translated to significant inhibition of xenograft tumor growth in vitro.By mapping the gene expression profiles,we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment.Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions.Specifically,we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin(ATF4/TXNIP/REDD1/mTOR)signaling critically controls GW3965‐mediated regulation of cell proliferation/death.The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.Conclusions:This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.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National Natural Science Foundation of China,Grant/Award Numbers:81270868,81472692,81573012。
文摘Background:Limited by difficulties in early detection and availabilities of effective treatments,pancreatic cancer is a highly malignant disease with poor prognosis.Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development,including cancer.In this study,we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor(LXR)agonist GW3965 in pancreatic cancer.Methods:Soft‐agar colony formation assay,xenograft tumors,Oligonucleotide microarray,Reverse transcription real‐time polymerase chain reaction,Western immunoblotting and Immunohistochemistry were used in this study.Results:We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability,inhibition of cell proliferation,stimulation of cell death,and suppression of colony formation,which translated to significant inhibition of xenograft tumor growth in vitro.By mapping the gene expression profiles,we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment.Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions.Specifically,we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin(ATF4/TXNIP/REDD1/mTOR)signaling critically controls GW3965‐mediated regulation of cell proliferation/death.The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.Conclusions:This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.
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.