Colorectal cancer(CRC)originates from biological events caused by gene mutations in normal intestinal epithelial cells(IECs).Sorting nexin 10(SNX10)is a tumor suppressor in CRC that is involved in regulating chaperone...Colorectal cancer(CRC)originates from biological events caused by gene mutations in normal intestinal epithelial cells(IECs).Sorting nexin 10(SNX10)is a tumor suppressor in CRC that is involved in regulating chaperone-mediated autophagy(CMA)activity,which is implicated in the pathogenesis of CRC and glycolysis process.DEP domain containing 5(DEPDC5)is a negative upstream regulator of mammalian target of rapamycin complex 1(mTORC1).a-hederin has anti-CRC effects.We previously found that SNX10 knockdown in normal human IECs promoted glycolysis and decreased DEPDC5 expression,which was reversed by a-hederin.However,the specific mechanism has not yet been elucidated.Here,we aimed to investigate the specific regulatory mechanism of SNX10 on DEPDC5 expression,and the action of a-hederin on this process.We demonstrated that the degradation of DEPDC5 protein was accelerated after SNX10 knockdown,causing the activation of the mTORC1 pathway,which relied on CMA activation and lysosomal function enhancement.SNX10 interacted with DEPDC5 and recruited it to lysosomes for degradation,and the glycolysis level mediated by mTORC1 was elevated.Additionally,these phenotypes in shSNX10 IECs were compromised by SNX10 rescue.Moreover,a-hederin bound to the SNX10 eDEPDC5 complex and impaired the interaction between SNX10 and DEPDC5,thereby inhibiting CMAmediated DEPDC5 degradation,impairing the aberrant activation of mTORC1 signaling,and eventually reversing the elevation of glycolysis caused by SNX10 knockdown.Overall,we are the first to demonstrate that SNX10-mediated DEPDC5 degradation is a novel strategy for malignant transformation of normal human IECs,with a-hederin regulated during this process.展开更多
The Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is a non-receptor tyrosine phosphatase and acts as a convergent node for oncogenic cell-signaling cascades.SHP2 has been recognized as a breakthrough an...The Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is a non-receptor tyrosine phosphatase and acts as a convergent node for oncogenic cell-signaling cascades.SHP2 has been recognized as a breakthrough antitumor therapeutic target.However,it is still elusive for the role of SHP2 in manipulating tumor microenvironment for malignancy.Here,we found that SHP2 activation in tumor-associated macrophages(TAMs)paralleled mammary carcinoma progression.Co-culture system and human breast cancer specimens also showed high levels of phosphorylated SHP2 in macrophages.Conditional SHP2 knockout or pharmacological SHP2 inhibition blocked mammary carcinoma growth and reduced metastasis.More importantly,tumor-derived IL-10 induced SHP2 phosphorylation in macrophages upon the tumor-macrophage interaction.SHP2 activation rendered macrophages an immunosuppressive phenotype and attenuated their responsiveness to type I interferon.IL-10 deficiency in mammary carcinoma cells caused tumor regression,which was accompanied by the reduction of SHP2 activation in TAMs.These findings suggest a protumorigenic role of SHP2 in the crosstalk between macrophages and mammary carcinoma cells in tumor microenvironments and reveal that targeting SHP2 in macrophages could be a therapeutic approach to improve anticancer therapy.展开更多
Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expre...Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.展开更多
基金supported by the National Natural Science Foundation of China(81973523).
文摘Colorectal cancer(CRC)originates from biological events caused by gene mutations in normal intestinal epithelial cells(IECs).Sorting nexin 10(SNX10)is a tumor suppressor in CRC that is involved in regulating chaperone-mediated autophagy(CMA)activity,which is implicated in the pathogenesis of CRC and glycolysis process.DEP domain containing 5(DEPDC5)is a negative upstream regulator of mammalian target of rapamycin complex 1(mTORC1).a-hederin has anti-CRC effects.We previously found that SNX10 knockdown in normal human IECs promoted glycolysis and decreased DEPDC5 expression,which was reversed by a-hederin.However,the specific mechanism has not yet been elucidated.Here,we aimed to investigate the specific regulatory mechanism of SNX10 on DEPDC5 expression,and the action of a-hederin on this process.We demonstrated that the degradation of DEPDC5 protein was accelerated after SNX10 knockdown,causing the activation of the mTORC1 pathway,which relied on CMA activation and lysosomal function enhancement.SNX10 interacted with DEPDC5 and recruited it to lysosomes for degradation,and the glycolysis level mediated by mTORC1 was elevated.Additionally,these phenotypes in shSNX10 IECs were compromised by SNX10 rescue.Moreover,a-hederin bound to the SNX10 eDEPDC5 complex and impaired the interaction between SNX10 and DEPDC5,thereby inhibiting CMAmediated DEPDC5 degradation,impairing the aberrant activation of mTORC1 signaling,and eventually reversing the elevation of glycolysis caused by SNX10 knockdown.Overall,we are the first to demonstrate that SNX10-mediated DEPDC5 degradation is a novel strategy for malignant transformation of normal human IECs,with a-hederin regulated during this process.
基金supported by National Key R&D Program of China(2022YFC3500202)National Natural Science Foundation of China(82230116,81974504,82103715)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202208).
文摘The Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is a non-receptor tyrosine phosphatase and acts as a convergent node for oncogenic cell-signaling cascades.SHP2 has been recognized as a breakthrough antitumor therapeutic target.However,it is still elusive for the role of SHP2 in manipulating tumor microenvironment for malignancy.Here,we found that SHP2 activation in tumor-associated macrophages(TAMs)paralleled mammary carcinoma progression.Co-culture system and human breast cancer specimens also showed high levels of phosphorylated SHP2 in macrophages.Conditional SHP2 knockout or pharmacological SHP2 inhibition blocked mammary carcinoma growth and reduced metastasis.More importantly,tumor-derived IL-10 induced SHP2 phosphorylation in macrophages upon the tumor-macrophage interaction.SHP2 activation rendered macrophages an immunosuppressive phenotype and attenuated their responsiveness to type I interferon.IL-10 deficiency in mammary carcinoma cells caused tumor regression,which was accompanied by the reduction of SHP2 activation in TAMs.These findings suggest a protumorigenic role of SHP2 in the crosstalk between macrophages and mammary carcinoma cells in tumor microenvironments and reveal that targeting SHP2 in macrophages could be a therapeutic approach to improve anticancer therapy.
基金This study was funded by National Natural Science Foundation of China(Nos.21937005 and 81974504)Natural Science Foundation of Jiangsu Province(No.BK 20191251,China)+1 种基金the Fundamental Research Funds for the Central Universities(China)National Key R&D·Program of China(No.2017YFA0506000).
文摘Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.
