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  • A Heme-Binding Transcription Factor BACH1 Regulates Lactate Catabolism Suggesting a Combined Therapy for Triple-Negative Breast Cancer.

A Heme-Binding Transcription Factor BACH1 Regulates Lactate Catabolism Suggesting a Combined Therapy for Triple-Negative Breast Cancer.

Cells (2022-04-13)
Joselyn Padilla, Bok-Soon Lee, Karen Zhai, Bethany Rentz, Tia Bobo, Norca Maritza Dowling, Jiyoung Lee
ABSTRACT

The oncogenic expression or mutation of tumor suppressors drives metabolic alteration, causing cancer cells to utilize diverse nutrients. Lactate is a known substrate for cancer cells, yet the regulatory mechanisms of lactate catabolism are limited. Here, we show that a heme-binding transcription factor, BACH1, negatively regulates lactate catabolic pathways in triple-negative breast cancer (TNBC) cells. BACH1 suppresses the transcriptional expression of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B, inhibiting lactate-mediated mitochondrial metabolism. In our studies, the depletion of BACH1 either genetically or pharmacologically increased the lactate use of TNBC cells, increasing their sensitivity to MCT1 inhibition. Thus, small inhibitory molecules (SR13800 and AZD3965) blocking MCT1 better suppressed the growth of BACH1-depleted TNBC cells than did the controls. Particularly, hemin treatment degrading BACH1 proteins induced lactate catabolism in TNBC cells, generating synthetic lethality with MCT1 inhibition. Our data indicates that targeting BACH1 generates metabolic vulnerability and increases sensitivity to lactate transporter inhibition, suggesting a potential novel combination therapy for cancer patients with TNBC.

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Millipore
Cocktail di inibitori delle proteasi, set III, senza EDTA, Protease inhibitor cocktail III, EDTA-free for inhibiting aspartic, cysteine, and serine proteases as well as aminopeptidases in mammalian cells and tissues.
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Anti-beta-Actin antibody, Rabbit monoclonal, recombinant, expressed in HEK 293 cells, clone RM112, purified immunoglobulin
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Anticorpo anti-trasportatore 1 dei monocarbossilati, Chemicon®, from rabbit
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Anti-MPC2 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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Anticorpo anti-carrier mitocondriale di piruvato 2 (BRP44), clone n/a, from mouse