Due to the poor metabolic conditions fomenting the emergence of the Warburg effect (WE) phenotype, abnormal glycometabolism has become a unique and fundamental research topic in the field of tumor biology. Moreover, hyperglycemia and hyperinsulinism are associated with poor outcomes in patients with breast cancer. However, there are a few studies on anticancer drugs targeting glycometabolism in breast cancer. We hypothesized that Oxabicycloheptene sulfonate (OBHS), a class of compounds that function as selective estrogen receptor modulators, may hold potential in a therapy for breast cancer glycometabolism. Here, we evaluated concentrations of glucose, glucose transporters, lactate, 40 metabolic intermediates, and glycolytic enzymes using an enzyme-linked immunosorbent assay, Western blotting, and targeted metabolomic analysis in, in vitro and in vivo breast cancer models. OBHS significantly inhibited the expression of glucose transporter 1 (GLUT1) via PI3K/Akt signaling pathway to suppress breast cancer progression and proliferation. Following an investigation of the modulatory effect of OBHS on breast cancer cells, we found that OBHS suppressed the glucose phosphorylation and oxidative phosphorylation of glycolytic enzymes, leading to the decreased biological synthesis of ATP. This study was novel in highlighting the role of OBHS in the remodeling of tumor glycometabolism in breast cancer, and this is worth further investigation of breast cancer in clinical trials.

2021-10-01·Biochemical and Biophysical Research Communications3区 · 生物学

OBHS impairs the viability of breast cancer via decreasing ERα and Atg13

3区 · 生物学

Article

作者: Zhou, Hai-Bing ; Huang, Jian ; Shen, Rong ; Zhou, Jiawei

Breast cancer (BRCA) is one of the most threatening cancer types, especially among the female population. 70% of breast cancer are estrogen receptor α (ERα) positive and endocrine therapy is effective to decrease breast cancer risk. Autophagy, a highly conserved cellular recycling process, has been regarded to serve a protective role in BRCA. Autophagy-related gene 13 (Atg13) is participated in autophagy and is critical to autophagy initiation. Briefly, we observed that ERα, a well-known transcription factor that can promote breast cancer cell proliferation, expressed higher in breast cancer tissues. Moreover, ERα had a significant positive correlation with Atg13 and may be able to regulate the transcription of Atg13 via binding the promoter region of Atg13. Surprisingly, Oxabicycloheptene sulfonate (OBHS), the drug that we reported as a selective estrogen receptor modulator (SERM) before, may have the ability to decrease the expression of ERα and suppress the autophagy. In conclusion. We found that ERα could be involved in autophagy by binding the promoter of Atg13, and compound OBHS may be able to affect the viability of breast cancer cells by decreasing the expression of ERα and Atg13.

2020-01-01·Cancer Letters

Three-dimensional oxabicycloheptene sulfonate targets the homologous recombination and repair programmes through estrogen receptor α antagonism

Article

作者: Fang, Pingping ; Zhou, Hai-Bing ; Liang, Kaiwei ; Wu, Jun ; Yan, Jing ; Huang, Jian

Selective estrogen receptor modulators (SERMs) are a class of structurally diverse compounds, which have been extensively used to treat hormone-responsive cancers due to their unique partially agonistic and antagonistic properties toward estrogen receptors. Our previous studies have identified a three-dimensional SERM, oxabicycloheptene sulfonate (OBHS), as an estrogen receptor α (ERα) ligand, which is effective for the prevention and treatment of estrogen-dependent endometriosis in vivo. Here, using genome-wide ChIP-seq and RNA-seq analysis, we report that OBHS rapidly induces genome-wide ERα occupancy and acts as a partial agonist and antagonist for ERα. Interestingly, OBHS downregulates the homologous recombination and repair (HRR) modules, resulting in increased DNA damage, apoptosis and cell cycle arrest, inducing synthetic lethality with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib through ERα antagonism. Mechanistically, OBHS impairs the RNA polymerase II (Pol II) loading at the promoters of estrogen-responsive HRR genes. Furthermore, combination therapy of OBHS with olaparib significantly reduces the tumour burden and delays the progression of breast cancer in vivo. Together, our studies not only characterise a novel SERM which uniquely targets the homologous recombination and repair programmes through ERα antagonism but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib for ERα-responsive cancers.

100 项与 Oxabicycloheptene sulfonate(University of Illinois at Urbana-Champaign) 相关的药物交易

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