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

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.

A Novel Therapeutic Target, BACH1, Regulates Cancer Metabolism.

BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

Effectiveness of probiotics, prebiotics, and prebiotic-like components in common functional foods.

The bioactive ingredients in commonly consumed foods include, but are not limited to, prebiotics, prebiotic-like components, probiotics, and postbiotics. The bioactive ingredients in functional foods have also been associated with beneficial effects on human health. For example, they aid in shaping of gut microflora and promotion of immunity. These functional components also contribute in preventing serious diseases such as cardiovascular malfunction and tumorigenesis. However, the specific mechanisms of these positive influences on human health are still under investigation. In this review, we aim to emphasize the major contents of probiotics, prebiotics, and prebiotic-like components commonly found in consumable functional foods, and we present an overview of direct and indirect benefits they provide on human health. The major contributors are certain families of metabolites, specifically short-chain fatty acids and polyunsaturated fatty acids produced by probiotics, and prebiotics, or prebiotic-like components such as flavonoids, polyphenols, and vitamins that are found in functional foods. These functional ingredients in foods influence the gut microbiota by stimulating the growth of beneficial microbes and the production of beneficial metabolites that, in turn, have direct benefits to the host, while also providing protection from pathogens and maintaining a balanced gut ecosystem. The complex interactions that arise among functional food ingredients, human physiology, the gut microbiota, and their respective metabolic pathways have been found to minimize several factors that contribute to the incidence of chronic disease, such as inflammation oxidative stress.

Antimicrobial Effect and Probiotic Potential of Phage Resistant Lactobacillus plantarum and its Interactions with Zoonotic Bacterial Pathogens.

Development of phage-resistant probiotic particularly Lactobacillus is an alternative approach to enhance their beneficial effects as in animal feed supplements. In this study, we developed phage-resistant Lactobacillus plantarum (LP+PR) mutant and compared their antimicrobial effects and probiotic potential against zoonotic bacterial pathogens including Salmonella enterica serovar Typhimurium, enterohemorrhagic Escherichia coli (EHEC), Staphylococcus aureus, and Listeria monocytogenes with phage-sensitive L. plantarum (LP) strain. LP+PR strain showed markedly higher growth rate than wild-type LP strain. In co-culture with LP+PR and in the presence of cell-free cultural supernatants (CFCSs) of LP+PR, the growth of S. Typhimurium, EHEC, S. aureus, and L. monocytogenes were reduced significantly (P < 0.05). The adhesion ability of LP+PR was slightly higher than the LP on human epithelial INT-407 cells. Most importantly, LP+PR strain significantly inhibited the adhesive and invasive abilities of all four zoonotic pathogens to INT-407 cells (P < 0.05). Moreover, real-time qPCR revealed that in the presence of LP+PR strain or its CFCSs, expression of virulence genes of these zoonotic bacterial pathogens were suppressed significantly (P < 0.05). These findings suggest that the LP+PR strain is capable of inhibiting major zoonotic bacterial pathogens efficiently and would be a potential candidate for industrial usage in animal production or fermentation.