PFKFB4 Promotes Angiogenesis Via IL-6/STAT5A/P-STAT5 Signaling in Breast Cancer

Overview

Journal J Cancer

Specialty Oncology

Date 2022 Jan 3

PMID 34976184

Citations 6

Authors

Dan Li

Jiaping Tang

Ruifang Gao

Jinxin Lan

Wenzhi Shen

Yanhua Liu

Yanan Chen

Hongwei Sun

Jie Yan

Yongwei Nie

Na Luo

Affiliations

Soon will be listed here.

Abstract

Breast cancer has become the most newly-diagnosed cancer and the 5 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 HUVEC tube formation or 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 and . Our findings suggest a potential strategy whereby 5-MPN may lead to an improved therapeutic outcome for breast cancer patients.

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References

Gopinathan G, Milagre C, Pearce O, Reynolds L, Hodivala-Dilke K, Leinster D . Interleukin-6 Stimulates Defective Angiogenesis. Cancer Res. 2015; 75(15):3098-107. PMC: 4527186. DOI: 10.1158/0008-5472.CAN-15-1227. View

Miller A, Nolan M, Choi J, Koga T, Shen X, Yue B . Lactate treatment causes NF-kappaB activation and CD44 shedding in cultured trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2007; 48(4):1615-21. DOI: 10.1167/iovs.06-1086. View

Dasgupta S, Rajapakshe K, Zhu B, Nikolai B, Yi P, Putluri N . Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 2018; 556(7700):249-254. PMC: 5895503. DOI: 10.1038/s41586-018-0018-1. View

Li X, Chen Z, Li Z, Huang G, Lin J, Wei Q . The metabolic role of PFKFB4 in androgen-independent growth in vitro and PFKFB4 expression in human prostate cancer tissue. BMC Urol. 2020; 20(1):61. PMC: 7268689. DOI: 10.1186/s12894-020-00635-0. View

Lugano R, Ramachandran M, Dimberg A . Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 2019; 77(9):1745-1770. PMC: 7190605. DOI: 10.1007/s00018-019-03351-7. View

Wang Q, Zeng F, Sun Y, Qiu Q, Zhang J, Huang W . Etk Interaction with PFKFB4 Modulates Chemoresistance of Small-cell Lung Cancer by Regulating Autophagy. Clin Cancer Res. 2017; 24(4):950-962. DOI: 10.1158/1078-0432.CCR-17-1475. View

Li W, Qian L, Lin J, Huang G, Hao N, Wei X . CD44 regulates prostate cancer proliferation, invasion and migration via PDK1 and PFKFB4. Oncotarget. 2017; 8(39):65143-65151. PMC: 5630319. DOI: 10.18632/oncotarget.17821. View

Huang S, Wu M, Shun C, Wang H, Lin M, Kuo M . Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma. J Biomed Sci. 2004; 11(4):517-27. DOI: 10.1007/BF02256101. View

Lu H, Chen S, You Z, Xie C, Huang S, Hu X . PFKFB4 negatively regulated the expression of histone acetyltransferase GCN5 to mediate the tumorigenesis of thyroid cancer. Dev Growth Differ. 2020; 62(2):129-138. DOI: 10.1111/dgd.12645. View

10.

Tormo A, Letellier M, Sharma M, Elson G, Crabe S, Gauchat J . IL-6 activates STAT5 in T cells. Cytokine. 2012; 60(2):575-82. DOI: 10.1016/j.cyto.2012.07.002. View

11.

Chesney J, Clark J, Klarer A, Imbert-Fernandez Y, Lane A, Telang S . Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth. Oncotarget. 2014; 5(16):6670-86. PMC: 4196155. DOI: 10.18632/oncotarget.2213. View

12.

Gao R, Liu Y, Li D, Xun J, Zhou W, Wang P . PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner. Cell Physiol Biochem. 2018; 50(6):2108-2123. DOI: 10.1159/000495055. View

13.

Xia Y, Shen S, Verma I . NF-κB, an active player in human cancers. Cancer Immunol Res. 2014; 2(9):823-30. PMC: 4155602. DOI: 10.1158/2326-6066.CIR-14-0112. View

14.

Comito G, Iscaro A, Bacci M, Morandi A, Ippolito L, Parri M . Lactate modulates CD4 T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene. 2019; 38(19):3681-3695. DOI: 10.1038/s41388-019-0688-7. View

15.

Luo N, Formisano L, Gonzalez-Ericsson P, Sanchez V, Dean P, Opalenik S . Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2. Oncoimmunology. 2018; 7(6):e1438106. PMC: 5975601. DOI: 10.1080/2162402X.2018.1438106. View

16.

Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z . The role of microenvironment in tumor angiogenesis. J Exp Clin Cancer Res. 2020; 39(1):204. PMC: 7526376. DOI: 10.1186/s13046-020-01709-5. View

17.

Folkman J . Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2003; 29(6 Suppl 16):15-8. DOI: 10.1053/sonc.2002.37263. View

18.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

19.

Minchenko O, Opentanova I, Minchenko D, Ogura T, Esumi H . Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1alpha activation. FEBS Lett. 2004; 576(1-2):14-20. DOI: 10.1016/j.febslet.2004.08.053. View

20.

Weis S, Cheresh D . Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011; 17(11):1359-70. DOI: 10.1038/nm.2537. View