Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity
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Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity. / Biswas, Dipsikha; Slade, Logan; Duffley, Luke; Mueller, Neil; Dao, Khoi; Mercer, Angella; Pakkiriswami, Shanmugasundaram; El Hiani, Yassine; Kienesberger, Petra C; Pulinilkunnil, Thomas.
In: Cell Death Discovery, Vol. 7, 241, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity
AU - Biswas, Dipsikha
AU - Slade, Logan
AU - Duffley, Luke
AU - Mueller, Neil
AU - Dao, Khoi
AU - Mercer, Angella
AU - Pakkiriswami, Shanmugasundaram
AU - El Hiani, Yassine
AU - Kienesberger, Petra C
AU - Pulinilkunnil, Thomas
PY - 2021
Y1 - 2021
N2 - Triple-negative breast cancers (TNBCs) are characterized by poor survival, prognosis, and gradual resistance to cytotoxic chemotherapeutics, like doxorubicin (DOX). The clinical utility of DOX is limited by its cardiotoxic and chemoresistant effects that manifest over time. To induce chemoresistance, TNBC rewires oncogenic gene expression and cell signaling pathways. Recent studies have demonstrated that reprogramming of branched-chain amino acids (BCAAs) metabolism facilitates tumor growth and survival. Branched-chain ketoacid dehydrogenase kinase (BCKDK), a regulatory kinase of the rate-limiting enzyme of the BCAA catabolic pathway, is reported to activate RAS/RAF/MEK/ERK signaling to promote tumor cell proliferation. However, it remains unexplored if BCKDK action remodels TNBC proliferation and survival per se and influences susceptibility to DOX-induced genotoxic stress. TNBC cells treated with DOX exhibited reduced BCKDK expression and intracellular BCKAs. Genetic and pharmacological inhibition of BCKDK in TNBC cell lines also showed a similar reduction in intracellular and secreted BCKAs. BCKDK silencing in TNBC cells downregulated mitochondrial metabolism genes, reduced electron complex protein expression, oxygen consumption, and ATP production. Transcriptome analysis of BCKDK silenced cells confirmed dysregulation of mitochondrial metabolic networks and upregulation of the apoptotic signaling pathway. Furthermore, BCKDK inhibition with concurrent DOX treatment exacerbated apoptosis, caspase activity, and loss of TNBC proliferation. Inhibition of BCKDK in TNBC also upregulated sestrin 2 and concurrently decreased mTORC1 signaling and protein synthesis. Overall, loss of BCKDK action in TNBC remodels BCAA flux, reduces protein translation triggering cell death, ATP insufficiency, and susceptibility to genotoxic stress.
AB - Triple-negative breast cancers (TNBCs) are characterized by poor survival, prognosis, and gradual resistance to cytotoxic chemotherapeutics, like doxorubicin (DOX). The clinical utility of DOX is limited by its cardiotoxic and chemoresistant effects that manifest over time. To induce chemoresistance, TNBC rewires oncogenic gene expression and cell signaling pathways. Recent studies have demonstrated that reprogramming of branched-chain amino acids (BCAAs) metabolism facilitates tumor growth and survival. Branched-chain ketoacid dehydrogenase kinase (BCKDK), a regulatory kinase of the rate-limiting enzyme of the BCAA catabolic pathway, is reported to activate RAS/RAF/MEK/ERK signaling to promote tumor cell proliferation. However, it remains unexplored if BCKDK action remodels TNBC proliferation and survival per se and influences susceptibility to DOX-induced genotoxic stress. TNBC cells treated with DOX exhibited reduced BCKDK expression and intracellular BCKAs. Genetic and pharmacological inhibition of BCKDK in TNBC cell lines also showed a similar reduction in intracellular and secreted BCKAs. BCKDK silencing in TNBC cells downregulated mitochondrial metabolism genes, reduced electron complex protein expression, oxygen consumption, and ATP production. Transcriptome analysis of BCKDK silenced cells confirmed dysregulation of mitochondrial metabolic networks and upregulation of the apoptotic signaling pathway. Furthermore, BCKDK inhibition with concurrent DOX treatment exacerbated apoptosis, caspase activity, and loss of TNBC proliferation. Inhibition of BCKDK in TNBC also upregulated sestrin 2 and concurrently decreased mTORC1 signaling and protein synthesis. Overall, loss of BCKDK action in TNBC remodels BCAA flux, reduces protein translation triggering cell death, ATP insufficiency, and susceptibility to genotoxic stress.
U2 - 10.1038/s41420-021-00602-0
DO - 10.1038/s41420-021-00602-0
M3 - Journal article
C2 - 34526485
VL - 7
JO - Cell Death Discovery
JF - Cell Death Discovery
SN - 2058-7716
M1 - 241
ER -
ID: 326359023