TY - JOUR
T1 - Medium-chain acyl-coa dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma
AU - Puca, Francesca
AU - Yu, Fei
AU - Bartolacci, Caterina
AU - Pettazzoni, Piergiorgio
AU - Carugo, Alessandro
AU - Huang-Hobbs, Emmet
AU - Liu, Jintan
AU - Zanca, Ciro
AU - Carbone, Federica
AU - Del Poggetto, Edoardo
AU - Gumin, Joy
AU - Dasgupta, Pushan
AU - Seth, Sahil
AU - Srinivasan, Sanjana
AU - Lang, Frederick F.
AU - Sulman, Erik P.
AU - Lorenzi, Philip L.
AU - Tan, Lin
AU - Shan, Mengrou
AU - Tolstyka, Zachary P.
AU - Kachman, Maureen
AU - Zhang, Li
AU - Gao, Sisi
AU - Deem, Angela K.
AU - Genovese, Giannicola
AU - Scaglioni, Pier Paolo
AU - Lyssiotis, Costas A.
AU - Viale, Andrea
AU - Draetta, Giulio F.
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research.
PY - 2021/11
Y1 - 2021/11
N2 - Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes mediumchain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM.
AB - Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes mediumchain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM.
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U2 - 10.1158/2159-8290.CD-20-1437
DO - 10.1158/2159-8290.CD-20-1437
M3 - Article
C2 - 34039636
AN - SCOPUS:85110257676
SN - 2159-8274
VL - 11
SP - 2904
EP - 2923
JO - Cancer discovery
JF - Cancer discovery
IS - 11
ER -