The Experts below are selected from a list of 3213 Experts worldwide ranked by ideXlab platform
Pike See Cheah - One of the best experts on this subject based on the ideXlab platform.
-
stearoyl coa desaturase is essential for regulation of endoplasmic reticulum homeostasis and tumor growth in glioblastoma cancer stem cells
Stem cell reports, 2019Co-Authors: Kelsey Pinkham, David J Park, Arsalan Hashemiaghdam, Aleksandar B Kirov, Isam Adam, Kamila Rosiak, Cintia Carla Da Hora, Jian Teng, Pike See CheahAbstract:Summary Inherent plasticity and various survival cues allow glioblastoma stem-like cells (GSCs) to survive and proliferate under intrinsic and extrinsic stress conditions. Here, we report that GSCs depend on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase (SCD1), which promotes ER homeostasis, cytoprotection, and tumor initiation. Pharmacological targeting of SCD1 is particularly toxic due to the accumulation of saturated fatty acids, which exacerbates ER stress, triggers apoptosis, impairs RAD51-mediated DNA repair, and achieves a remarkable therapeutic outcome with 25%–100% cure rate in xenograft mouse models. Mechanistically, divergent cell fates under varying levels of ER stress are primarily controlled by the ER sensor IRE1, which either promotes SCD1 transcriptional activation or converts to apoptotic signaling when SCD1 activity is impaired. Taken together, the dependence of GSCs on fatty acid desaturation presents an Exploitable Vulnerability to target glioblastoma.
-
Stearoyl CoA Desaturase Is Essential for Regulation of Endoplasmic Reticulum Homeostasis and Tumor Growth in Glioblastoma Cancer Stem Cells
Elsevier, 2019Co-Authors: Kelsey Pinkham, David J Park, Arsalan Hashemiaghdam, Aleksandar B Kirov, Isam Adam, Kamila Rosiak, Cintia Carla Da Hora, Jian Teng, Pike See Cheah, Litia CarvalhoAbstract:Summary: Inherent plasticity and various survival cues allow glioblastoma stem-like cells (GSCs) to survive and proliferate under intrinsic and extrinsic stress conditions. Here, we report that GSCs depend on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase (SCD1), which promotes ER homeostasis, cytoprotection, and tumor initiation. Pharmacological targeting of SCD1 is particularly toxic due to the accumulation of saturated fatty acids, which exacerbates ER stress, triggers apoptosis, impairs RAD51-mediated DNA repair, and achieves a remarkable therapeutic outcome with 25%–100% cure rate in xenograft mouse models. Mechanistically, divergent cell fates under varying levels of ER stress are primarily controlled by the ER sensor IRE1, which either promotes SCD1 transcriptional activation or converts to apoptotic signaling when SCD1 activity is impaired. Taken together, the dependence of GSCs on fatty acid desaturation presents an Exploitable Vulnerability to target glioblastoma. : In this article, Pinkham and colleagues demonstrate that the fatty acid desaturase stearoyl CoA desaturase (SCD1) is essential for the maintenance of glioblastoma cancer stem cells. SCD1 is activated by ER stress and exerts a cytoprotective function by regulating ER homeostasis, thus favoring survival and tumor growth. Pharmacological targeting of SCD1 exhibits potent therapeutic efficacy in brain tumor mouse models. Keywords: glioblastoma, glioma stem cells, stearoyl CoA desaturase, ER stress, unfolded protein response, inositol-requiring enzyme
Hiroaki Wakimoto - One of the best experts on this subject based on the ideXlab platform.
-
Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma
Cancer cell, 2017Co-Authors: Christian Braun, Monica Stanciu, Paul L. Boutz, Jesse C. Patterson, David Calligaris, Fumi Higuchi, Rachit Neupane, Silvia Fenoglio, Daniel P. Cahill, Hiroaki WakimotoAbstract:Summary Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis. We further show that DI programs are evolutionarily conserved and operate during neurogenesis, suggesting that they represent a physiological regulatory mechanism. Collectively, these findings reveal a PRMT5-regulated DI-splicing program as an Exploitable cancer Vulnerability.
Susan Lindquist - One of the best experts on this subject based on the ideXlab platform.
-
Inhibiting mitochondrial phosphate transport as an unexploited antifungal strategy
Nature Chemical Biology, 2018Co-Authors: Catherine A Mclellan, Benjamin M Vincent, Norma V Solis, Alex K Lancaster, Lucas B Sullivan, Cathy L Hartland, Willmen Youngsaye, Scott G Filler, Luke Whitesell, Susan LindquistAbstract:The development of effective antifungal therapeutics remains a formidable challenge because of the close evolutionary relationship between humans and fungi. Mitochondrial function may present an Exploitable Vulnerability because of its differential utilization in fungi and its pivotal roles in fungal morphogenesis, virulence, and drug resistance already demonstrated by others. We now report mechanistic characterization of ML316, a thiohydantoin that kills drug-resistant Candida species at nanomolar concentrations through fungal-selective inhibition of the mitochondrial phosphate carrier Mir1. Using genetic, biochemical, and metabolomic approaches, we established ML316 as the first Mir1 inhibitor. Inhibition of Mir1 by ML316 in respiring yeast diminished mitochondrial oxygen consumption, resulting in an unusual metabolic catastrophe marked by citrate accumulation and death. In a mouse model of azole-resistant oropharyngeal candidiasis, ML316 reduced fungal burden and enhanced azole activity. Targeting Mir1 could provide a new, much-needed therapeutic strategy to address the rapidly rising burden of drug-resistant fungal infection. A potent inhibitor of the conditionally essential mitochondrial phosphate carrier protein Mir1 in the fungi Candida albicans diminishes mitochondrial oxygen consumption and causes dramatic changes in concentrations of citrate and succinate.
Christian Braun - One of the best experts on this subject based on the ideXlab platform.
-
Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma
Cancer cell, 2017Co-Authors: Christian Braun, Monica Stanciu, Paul L. Boutz, Jesse C. Patterson, David Calligaris, Fumi Higuchi, Rachit Neupane, Silvia Fenoglio, Daniel P. Cahill, Hiroaki WakimotoAbstract:Summary Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis. We further show that DI programs are evolutionarily conserved and operate during neurogenesis, suggesting that they represent a physiological regulatory mechanism. Collectively, these findings reveal a PRMT5-regulated DI-splicing program as an Exploitable cancer Vulnerability.
Kelsey Pinkham - One of the best experts on this subject based on the ideXlab platform.
-
stearoyl coa desaturase is essential for regulation of endoplasmic reticulum homeostasis and tumor growth in glioblastoma cancer stem cells
Stem cell reports, 2019Co-Authors: Kelsey Pinkham, David J Park, Arsalan Hashemiaghdam, Aleksandar B Kirov, Isam Adam, Kamila Rosiak, Cintia Carla Da Hora, Jian Teng, Pike See CheahAbstract:Summary Inherent plasticity and various survival cues allow glioblastoma stem-like cells (GSCs) to survive and proliferate under intrinsic and extrinsic stress conditions. Here, we report that GSCs depend on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase (SCD1), which promotes ER homeostasis, cytoprotection, and tumor initiation. Pharmacological targeting of SCD1 is particularly toxic due to the accumulation of saturated fatty acids, which exacerbates ER stress, triggers apoptosis, impairs RAD51-mediated DNA repair, and achieves a remarkable therapeutic outcome with 25%–100% cure rate in xenograft mouse models. Mechanistically, divergent cell fates under varying levels of ER stress are primarily controlled by the ER sensor IRE1, which either promotes SCD1 transcriptional activation or converts to apoptotic signaling when SCD1 activity is impaired. Taken together, the dependence of GSCs on fatty acid desaturation presents an Exploitable Vulnerability to target glioblastoma.
-
Stearoyl CoA Desaturase Is Essential for Regulation of Endoplasmic Reticulum Homeostasis and Tumor Growth in Glioblastoma Cancer Stem Cells
Elsevier, 2019Co-Authors: Kelsey Pinkham, David J Park, Arsalan Hashemiaghdam, Aleksandar B Kirov, Isam Adam, Kamila Rosiak, Cintia Carla Da Hora, Jian Teng, Pike See Cheah, Litia CarvalhoAbstract:Summary: Inherent plasticity and various survival cues allow glioblastoma stem-like cells (GSCs) to survive and proliferate under intrinsic and extrinsic stress conditions. Here, we report that GSCs depend on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase (SCD1), which promotes ER homeostasis, cytoprotection, and tumor initiation. Pharmacological targeting of SCD1 is particularly toxic due to the accumulation of saturated fatty acids, which exacerbates ER stress, triggers apoptosis, impairs RAD51-mediated DNA repair, and achieves a remarkable therapeutic outcome with 25%–100% cure rate in xenograft mouse models. Mechanistically, divergent cell fates under varying levels of ER stress are primarily controlled by the ER sensor IRE1, which either promotes SCD1 transcriptional activation or converts to apoptotic signaling when SCD1 activity is impaired. Taken together, the dependence of GSCs on fatty acid desaturation presents an Exploitable Vulnerability to target glioblastoma. : In this article, Pinkham and colleagues demonstrate that the fatty acid desaturase stearoyl CoA desaturase (SCD1) is essential for the maintenance of glioblastoma cancer stem cells. SCD1 is activated by ER stress and exerts a cytoprotective function by regulating ER homeostasis, thus favoring survival and tumor growth. Pharmacological targeting of SCD1 exhibits potent therapeutic efficacy in brain tumor mouse models. Keywords: glioblastoma, glioma stem cells, stearoyl CoA desaturase, ER stress, unfolded protein response, inositol-requiring enzyme
