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The breast cancer oncogene IKK? coordinates mitochondrial function and serine metabolism

ABSTRACT: I?B kinase ? (IKK?) is a key molecule at the crossroads of inflammation and cancer. Known to regulate cytokine secretion via NF?B and IRF3, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKK? remodels cellular metabolism is currently unknown. Here we used metabolic tracer analysis to show that IKK? orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and consequently serine biosynthesis independently of its canonical signalling role. We found that IKK? upregulates the serine biosynthesis pathway (SBP) indirectly, by limiting glucose derived pyruvate utilisation in the TCA cycle, inhibiting oxidative phosphorylation. Inhibition of mitochondrial function induces Activating Transcription Factor 4 (ATF4), which in turn drives upregulation of the expression of SBP genes. Importantly, pharmacological reversal of the IKK?-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a highly proliferative set of ER negative, basal breast tumours, IKK? and PSAT1 are both overexpressed, corroborating the link between IKK? and the SBP in the clinical context.

SUBMITTER: Ruoyan Xu

PROVIDER: S-SCDT-EMBOR-2019-48260-T | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Triple negative breast cancer (TNBC) patients have high risk of recurrence and metastasis, and current treatment options remain limited. Cancer stem-like cells (CSCs) have been linked to cancer initiation, progression and chemotherapy resistance. Notch signaling is a key pathway regulating TNBC CSC survival. Treatment of TNBC with PI3K or mTORC1/2 inhibitors results in drug-resistant, Notch-dependent CSC. However, downstream mechanisms and potentially druggable Notch effectors in TNBC CSCs are largely unknown. We studied the role of the AKT pathway and mitochondrial metabolism downstream of Notch signaling in TNBC CSC from cell lines representative of different TNBC molecular subtypes as well as a novel patient-derived model. We demonstrate that exposure of TNBC cells to recombinant Notch ligand Jagged1 leads to rapid AKT phosphorylation in a Notch1-dependent but RBP-J? independent fashion. This requires mTOR and IKK?. Jagged1 also stimulates mitochondrial respiration and fermentation in an AKT- and IKK-dependent fashion. Notch1 co-localizes with mitochondria in TNBC cells. Pharmacological inhibition of Notch cleavage by gamma secretase inhibitor PF-03084014 in combination with AKT inhibitor MK-2206 or IKK-targeted NF-?B inhibitor Bay11-7082 blocks secondary mammosphere formation from sorted CD90hi or CD44+CD24low (CSCs) cells. A TNBC patient-derived model gave comparable results. Besides mitochondrial oxidative metabolism, Jagged1 also triggers nuclear, NF-?B-dependent transcription of anti-apoptotic gene cIAP-2. This requires recruitment of Notch1, IKK? and NF-?B to the cIAP-2 promoter. Our observations support a model where Jagged1 triggers IKK?-dependent, mitochondrial and nuclear Notch1 signals that stimulate AKT phosphorylation, oxidative metabolism and transcription of survival genes in PTEN wild-type TNBC cells. These data suggest that combination treatments targeting the intersection of the Notch, AKT and NF-?B pathways have potential therapeutic applications against CSCs in TNBC cases with Notch1 and wild-type PTEN expression.

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The breast cancer oncogene IKK? coordinates mitochondrial function and serine metabolism

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