Epithelioid angiomyolipoma (EAML) is a rare morphologic variant of classic angiomyolipoma (AML), showing potentially malignant phenotype. AML is a benign mesenchymal tumor, which shows frequent inactivating mutations ...Epithelioid angiomyolipoma (EAML) is a rare morphologic variant of classic angiomyolipoma (AML), showing potentially malignant phenotype. AML is a benign mesenchymal tumor, which shows frequent inactivating mutations of?TSC1 (encodes harmartin) or?TSC2 (encodes tuberin) genes. Disruption of harmatin-tuberin complex and subsequent inappropriate activation of mTOR pathway is a distinct feature of AML. Thus, mTOR pathway inhibitors have shown significant clinical response in AML. Compared to the great success of mTOR inhibitors in AML, there is no standard therapy for EAML yet. Here, we present a patient with EAML who responded well to mTOR inhibitor (temsirolimus) but suffered rapid disease progression after cessation of temsirolimus. In addition, we performed Cancer Hotspot Panel (Ion AmpliSeqTM) analysis to identify novel tumorigenic properties of EAML. Of note, Cancer Hotspot Panel analysis revealed novel missense mutation in?SMARCB1 (c.1119-41G > A) tumor suppressor gene and subsequent immunohistochemistry analysis also revealed weak and partial losses ofSMARCB1/INI1 protein in nuclei of tumor cells. In this study, we suggest that mTOR inhibitors also can be effective against EAML. However, the long-term efficacy of mTOR inhibitors in EAML needs to be supported in further studies. Furthermore, we speculate that the newly found missense mutation ofSMARCB1/INI1 gene can be the possible novel tumorigenic properties of EAML and highlights the possibility of further novel targeted therapy beyond mTOR inhibitors in EAML.展开更多
Objective To examine the effects of temsirolimus, an inhibitor of mammalian target of rapamycin,on bladder cancer cell lines T24 and BIU-87 in vitro and in vivo for purpose of evaluating the probability of mTOR target...Objective To examine the effects of temsirolimus, an inhibitor of mammalian target of rapamycin,on bladder cancer cell lines T24 and BIU-87 in vitro and in vivo for purpose of evaluating the probability of mTOR targeted therapy for bladder cancer. Methods After展开更多
Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation.While lipid radical elimination reaction catalyzed by glutathione peroxidase 4(GPX4)is a major anti-...Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation.While lipid radical elimination reaction catalyzed by glutathione peroxidase 4(GPX4)is a major anti-ferroptosis mechanism,inhibiting this pathway pharmaceutically shows promise as an antitumor strategy.However,certain tumor cells exhibit redundancy in lipid radical elimination pathways,rendering them unresponsive to GPX4 inhibitors.In this study,we conducted screens across different cancer cell lines and Food and Drug Administration-approved drugs,leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells.Mechanistically,temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1(FSP1)enzyme.Notably,while temsirolimus is recognized as a potent mammalian target of rapamycin(mTOR)inhibitor,its ferroptosis-inducing effect is primarily attributed to the inhibition of FSP1 rather than mTOR activity.By employing in vitro colony formation assays and in vivo tumor xenograft models,we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression.This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis.In conclusion,our findings underscore the potential of combining multitarget ferroptosis-inducing agents to circumvent the resistance to ferroptosis of liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer,which also deserves further investigation in translational medicine.展开更多
文摘Epithelioid angiomyolipoma (EAML) is a rare morphologic variant of classic angiomyolipoma (AML), showing potentially malignant phenotype. AML is a benign mesenchymal tumor, which shows frequent inactivating mutations of?TSC1 (encodes harmartin) or?TSC2 (encodes tuberin) genes. Disruption of harmatin-tuberin complex and subsequent inappropriate activation of mTOR pathway is a distinct feature of AML. Thus, mTOR pathway inhibitors have shown significant clinical response in AML. Compared to the great success of mTOR inhibitors in AML, there is no standard therapy for EAML yet. Here, we present a patient with EAML who responded well to mTOR inhibitor (temsirolimus) but suffered rapid disease progression after cessation of temsirolimus. In addition, we performed Cancer Hotspot Panel (Ion AmpliSeqTM) analysis to identify novel tumorigenic properties of EAML. Of note, Cancer Hotspot Panel analysis revealed novel missense mutation in?SMARCB1 (c.1119-41G > A) tumor suppressor gene and subsequent immunohistochemistry analysis also revealed weak and partial losses ofSMARCB1/INI1 protein in nuclei of tumor cells. In this study, we suggest that mTOR inhibitors also can be effective against EAML. However, the long-term efficacy of mTOR inhibitors in EAML needs to be supported in further studies. Furthermore, we speculate that the newly found missense mutation ofSMARCB1/INI1 gene can be the possible novel tumorigenic properties of EAML and highlights the possibility of further novel targeted therapy beyond mTOR inhibitors in EAML.
文摘Objective To examine the effects of temsirolimus, an inhibitor of mammalian target of rapamycin,on bladder cancer cell lines T24 and BIU-87 in vitro and in vivo for purpose of evaluating the probability of mTOR targeted therapy for bladder cancer. Methods After
基金funded by grants from the National Key R&D Program of China(2020YFA0803202 to D.Y.)the National Natural Science Foundation of China(82225036 and 31821002 to D.Y.,32101011 to P.W.).
文摘Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation.While lipid radical elimination reaction catalyzed by glutathione peroxidase 4(GPX4)is a major anti-ferroptosis mechanism,inhibiting this pathway pharmaceutically shows promise as an antitumor strategy.However,certain tumor cells exhibit redundancy in lipid radical elimination pathways,rendering them unresponsive to GPX4 inhibitors.In this study,we conducted screens across different cancer cell lines and Food and Drug Administration-approved drugs,leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells.Mechanistically,temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1(FSP1)enzyme.Notably,while temsirolimus is recognized as a potent mammalian target of rapamycin(mTOR)inhibitor,its ferroptosis-inducing effect is primarily attributed to the inhibition of FSP1 rather than mTOR activity.By employing in vitro colony formation assays and in vivo tumor xenograft models,we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression.This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis.In conclusion,our findings underscore the potential of combining multitarget ferroptosis-inducing agents to circumvent the resistance to ferroptosis of liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer,which also deserves further investigation in translational medicine.
