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Baicalein resensitizes tamoxifen-resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia-inducible factor-1α.

ABSTRACT: Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM-resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM-resistant cells. It also enhanced the TAM-induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan-Meier plotter database showed that HIF-1α expression was inversely correlated with TAM therapeutic response in NCI-60 cancer cells and breast cancer patients. HIF-1α expression was increased in TAM-resistant cells due to an increase in mRNA levels and reduced ubiquitin-mediated degradation. Baicalein reduced HIF-1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase-mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia-response element, and transcriptional activity of HIF-1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF-1α-targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF-1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM-induced mitochondrial apoptotic pathway. The HIF-1α stabilizer dimethyloxallyl glycine prevented the baicalein-induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM-induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF-1α-mediated aerobic glycolysis and mitochondrial dysfunction.

SUBMITTER: Chen Y

PROVIDER: S-EPMC8567056 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glycolysis, a series of oxidative reactions used to metabolize glucose and provide energy to host cells, is also required for respiratory syncytial virus (RSV) infection. However, the role of glycolysis during RSV infection and its underlying molecular mechanisms remain to be further explored. In this study, we investigated the function of hypoxia-inducible factor (HIF)-1α-mediated glycolysis in HEp-2 cells and mouse models during RSV infection. The results showed that RSV infection activated the insulin receptor (IR)-PI3K-Akt axis, upregulated the translation and activity of HIF-1α, increased the expression of glucose transporters (Glut1, Glut3, and Glut4), hexokinase (HK) 1 and 2, and platelet-type phosphofructokinase (PFKP), and promoted glucose uptake and glycolysis. In addition, mitochondrial damage induced by RSV resulted in the generation of large amounts of reactive oxygen species (ROS) in infected cells, which contributed to the stabilization and activation of HIF-1α. An energy map of the glycolytic ATP production rate (Glyco-ATP) versus the mitochondrial ATP production rate (mito-ATP) confirmed a switch from oxidative phosphorylation (OXPHOS) to glycolysis. Inhibition of IR-PI3K-Akt signaling, ROS, or HIF-1α effectively reversed the RSV-induced increase in glycolysis by blocking HIF-1α activation. Importantly, HIF-1α-mediated glycolysis provided energy for the production of progeny RSV virions. The production of infectious virions was nearly abolished after knocking down HIF-1α. PX-478, an orally active HIF-1α inhibitor, effectively inhibited RSV infection in vivo. Collectively, these results indicate the role of HIF-1α-mediated glycolysis in RSV infection and highlight HIF-1α as a potential target for anti-RSV drug development. IMPORTANCE Respiratory syncytial virus (RSV) is the leading etiological agent of lower respiratory tract illness. However, efficacious vaccines or antiviral drugs for treating RSV infections are currently not available. Indeed, RSV depends on host cells to provide energy needed to produce progeny virions. Glycolysis is a series of oxidative reactions used to metabolize glucose and provide energy to host cells. Therefore, glycolysis may be helpful for RSV infection. In this study, we show that RSV increases glycolysis by inducing the stabilization, transcription, translation, and activation of hypoxia-inducible factor (HIF)-1α in infected cells, which is important for the production of progeny RSV virions. This study contributes to understanding the molecular mechanism by which HIF-1α-mediated glycolysis controls RSV infection and reveals an effective target for the development of highly efficient anti-RSV drugs.

Project description:ObjectivesReprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose-dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. The type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration-resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. However, whether PRKAR2B regulates glucose metabolism in prostate cancer remains largely unknown.Materials and methodsLoss-of-function and gain-of-function studies were used to investigate the regulatory role of PRKAR2B in aerobic glycolysis. Real-time qPCR, Western blotting, luciferase reporter assay and chromatin immunoprecipitation were employed to determine the underlying mechanisms.ResultsPRKAR2B was sufficient to enhance the Warburg effect as demonstrated by glucose consumption, lactate production and extracellular acidification rate. Mechanistically, loss-of-function and gain-of-function studies showed that PRKAR2B was critically involved in the tumour growth of prostate cancer. PRKAR2B was able to increase the expression level of hypoxia-inducible factor 1α (HIF-1α), which is a key mediator of the Warburg effect. Moreover, we uncovered that HIF-1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B-mediated tumour-promoting effect. Similar phenomenon was noticed by genetic silencing of HIF-1α.ConclusionsOur study identified that PRKAR2B-HIF-1α loop enhances the Warburg effect to enable growth advantage in prostate cancer.

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Baicalein resensitizes tamoxifen-resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia-inducible factor-1α.

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