AbstractThe treatment of multiple myeloma (MM) patients has been dramatically changed by the introduction of new agents; however, many patients relapse. Hypoxia is a critical component of the bone-marrow microenvironment. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) is responsible for maintaining cellular levels of fructose-2,6-bisphosphate, which regulates glycolysis. We found that the gene expressions of PFKFB3 and PFKFB4 were elevated under hypoxic conditions. Treatments with the PFKFB3 inhibitor, PFK158, and PFKFB4 inhibitor, 5MPN, were found to inhibit the growth of myeloma cells. The combined treatment of myeloma cells with carfilzomib and PFK158 or 5MPN was more cytotoxic than either drug alone. Caspase 3/7 activity and cellular cytotoxicity were also increased. In addition, the combined treatment was effective in the bortezomib-resistant cell line. Our data also suggest that administration of PFKFB3 and PFKFB4 inhibitors may be a powerful strategy against myeloma cells and to enhance the cytotoxic effects of proteasome inhibitors in hypoxic conditions.

2022-01-01·Journal of Cancer3区 · 医学

PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer

3区 · 医学

ArticleOA

作者: Sun, Hongwei ; Lan, Jinxin ; Shen, Wenzhi ; Liu, Yanhua ; Chen, Yanan ; Gao, Ruifang ; Nie, Yongwei ; Li, Dan ; Yan, Jie ; Luo, Na ; Tang, Jiaping

Breast cancer has become the most newly-diagnosed cancer and the 5^th leading cause of cancer death worldwide. The 5-year survival rate of breast cancer is about 90%. However, the 5-year survival rate drops to <30% when metastasis to distant sites occurs. The blood vessel formation (i.e., angiogenesis) plays a crucial role during the metastatic process. In this study, we investigated the role of PFKFB4 in angiogenesis of breast cancer. Employing in vitro HUVEC tube formation or in vivo orthotopic mouse model, and gene editing or specific small inhibitors strategy, and utilizing qPCR, western blot, ELISA, or immunofluorescent/immunohistochemistry staining methods, we found the following: 1) PFKFB4 upregulates IL-6 expression via NF-κB signaling in breast cancer cells; 2) PFKFB4-induced lactate secretion contributes to NF-κB activation in breast cancer cells; 3) IL-6 elicits angiogenesis via STAT5A/P-STAT5 in HUVEC; 4) 5-MPN (a specific PFKFB4 inhibitor) suppresses angiogenesis in vitro and in vivo. Our findings suggest a potential strategy whereby 5-MPN may lead to an improved therapeutic outcome for breast cancer patients.

2018-01-01·Theranostics1区 · 医学

CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism

1区 · 医学

ArticleOA

作者: Liu, Chen ; Luo, Na ; Zhou, Wei ; Stupack, Dwayne G ; Wang, Juan ; Xun, Jing ; Qiao, Huan ; Shen, Wenzhi ; Gao, Ruifang ; Li, Xiru ; Li, Jun ; Li, Dan

CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44^high cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing. Methods: Gain- and loss-of-function methods in different models were used to investigate the effects of CD44 on breast cancer stemness. Cancer stemness was analyzed by detecting SOX2, OCT4 and NANOG expression, ALDH activity, side population (SP) and sphere formation. Glucose consumption, lactate secretion and reactive oxygen species (ROS) levels were detected to assess glycolysis. Western blot, immunohistochemical staining, ELISA and TCGA dataset analysis were performed to determine the association of CD44ICD and PFKFB4 with clinical cases. A PFKFB4 inhibitor, 5MPN, was used in a xenograft model to inhibit breast cancer development. Results: In this report, we found that the shortest CD44 isoform (CD44s) inhibits breast cancer stemness, whereas the cleaved product of CD44 (CD44ICD) promotes breast cancer stemness. Furthermore, CD44ICD interacts with CREB and binds to the promoter region of PFKFB4, thereby regulating PFKFB4 transcription and expression. The resultant PFKFB4 expression facilitates the glycolysis pathway (vis-à-vis oxidative phosphorylation) and promotes stemness of breast cancer. In addition, we found that CD44ICD and PFKFB4 expressions are generally up-regulated in the tumor portion of breast cancer patient samples. Most importantly, we found that 5MPN (a selective inhibitor of PFKFB4) suppresses CD44ICD-induced tumor development. Conclusion: CD44ICD promotes breast cancer stemness via PFKFB4-mediated glycolysis, and therapies that target PFKFB4 (e.g., 5MPN therapy) may lead to improved outcomes for cancer patients.

100 项与 5-MPN 相关的药物交易

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