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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2016

01-11-2016 | Preclinical study

Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2+ breast cancer

Authors: Julie O’Neal, Amy Clem, Lindsey Reynolds, Susan Dougherty, Yoannis Imbert-Fernandez, Sucheta Telang, Jason Chesney, Brian F. Clem

Published in: Breast Cancer Research and Treatment | Issue 1/2016

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Abstract

Purpose

Human epidermal growth factor receptor-2 (HER2) has been implicated in the progression of multiple tumor types, including breast cancer, and many downstream effectors of HER2 signaling are primary regulators of cellular metabolism, including Ras and Akt. A key downstream metabolic target of Ras and Akt is the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 isozyme (PFKFB3), whose product, fructose-2,6-bisphosphate (F26BP), is a potent allosteric activator of a rate-limiting enzyme in glycolysis, 6-phosphofructo-1-kinase (PFK-1). We postulate that PFKFB3 may be regulated by HER2 and contribute to HER2-driven tumorigenicity.

Methods

Immunohistochemistry and Kaplan–Meier analysis of HER2+ patient samples investigated the relevance of PFKFB3 in HER2+ breast cancer. In vitro genetic and pharmacological inhibition of PFKFB3 was utilized to determine effects on HER2+ breast cancer cells, while HER2 antagonist treatment assessed the mechanistic regulation on PFKFB3 expression and glucose metabolism. Administration of a PFKFB3 inhibitor in a HER2-driven transgenic breast cancer model evaluated this potential therapeutic approach in vivo.

Results

PFKFB3 is elevated in human HER2+ breast cancer and high PFKFB3 transcript correlated with poorer progression-free (PFS) and distant metastatic-free (DFMS) survival. Constitutive HER2 expression led to elevated PFKFB3 expression and increased glucose metabolism, while inhibition of PFKFB3 suppressed glucose uptake, F26BP, glycolysis, and selectively decreased the growth of HER2-expressing breast cancer cells. In addition, treatment with lapatinib, an FDA-approved HER2 inhibitor, decreased PFKFB3 expression and glucose metabolism in HER2+ cells. In vivo administration of a PFKFB3 antagonist significantly suppressed the growth of HER2-driven breast tumors and decreased 18F-2-deoxy-glucose uptake.

Conclusions

Taken together, these data support the potential clinical utility of PFKFB3 inhibitors as chemotherapeutic agents against HER2+ breast cancer.
Appendix
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Literature
1.
2.
Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95CrossRefPubMed
3.
4.
5.
Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330(6009):1340–1344CrossRefPubMed
6.
McCann AH, Dervan PA, O’Regan M, Codd MB, Gullick WJ, Tobin BM, Carney DN (1991) Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer. Cancer Res 51(12):3296–3303PubMed
7.
van de Vijver M, van de Bersselaar R, Devilee P, Cornelisse C, Peterse J, Nusse R (1987) Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Mol Cell Biol 7(5):2019–2023CrossRefPubMedPubMedCentral
8.
Hynes NE, Stern DF (1994) The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198(2–3):165–184PubMed
9.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182CrossRefPubMed
10.
Chesney J, Telang S (2013) Regulation of glycolytic and mitochondrial metabolism by ras. Curr Pharm Biotechnol 14(3):251–260CrossRefPubMed
11.
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM et al (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64(11):3892–3899CrossRefPubMed
12.
Robey RB, Hay N (2009) Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 19(1):25–31CrossRefPubMed
13.
Zhao YH, Zhou M, Liu H, Ding Y, Khong HT, Yu D, Fodstad O, Tan M (2009) Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene 28(42):3689–3701CrossRefPubMed
14.
Cheyne RW, Trembleau L, McLaughlin A, Smith TA (2011) Changes in 2-fluoro-2-deoxy-d-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab. Nucl Med Biol 38(3):339–346CrossRefPubMed
15.
Van Schaftingen E, Hue L, Hers HG (1980) Control of the fructose-6-phosphate/fructose 1,6-bisphosphate cycle in isolated hepatocytes by glucose and glucagon. Role of a low-molecular-weight stimulator of phosphofructokinase. Biochem J 192(3):887–895CrossRefPubMedPubMedCentral
16.
Van Schaftingen E, Hue L, Hers HG (1980) Fructose 2,6-bisphosphate, the probably structure of the glucose- and glucagon-sensitive stimulator of phosphofructokinase. Biochem J 192(3):897–901CrossRefPubMedPubMedCentral
17.
Yalcin A, Telang S, Clem B, Chesney J (2009) Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp Mol Pathol 86(3):174–179CrossRefPubMed
18.
Ros S, Schulze A (2013) Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer & metabolism 1(1):8CrossRef
19.
Sakakibara R, Kato M, Okamura N, Nakagawa T, Komada Y, Tominaga N, Shimojo M, Fukasawa M (1997) Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase. J Biochem 122(1):122–128CrossRefPubMed
20.
Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z, Mitchell R, Bucala R (2002) High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res 62(20):5881–5887PubMed
21.
Telang S, Yalcin A, Clem AL, Bucala R, Lane AN, Eaton JW, Chesney J (2006) Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25(55):7225–7234CrossRefPubMed
22.
Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J et al (2008) Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther 7(1):110–120CrossRefPubMed
23.
Clem BF, O’Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA 2nd, Klarer AC, Redman R, Miller DM, Trent JO et al (2013) Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther 12(8):1461–1470CrossRefPubMedPubMedCentral
24.
Van Schaftingen E, Lederer B, Bartrons R, Hers HG (1982) A kinetic study of pyrophosphate: fructose-6-phosphate phosphotransferase from potato tubers. Application to a microassay of fructose 2,6-bisphosphate. Eur J Biochem 129(1):191–195CrossRefPubMed
25.
Imbert-Fernandez Y, Clem BF, O’Neal J, Kerr DA, Spaulding R, Lanceta L, Clem AL, Telang S, Chesney J (2014) Estradiol stimulates glucose metabolism via 6-phosphofructo-2-kinase (PFKFB3). J Biol Chem 289(13):9440–9448CrossRefPubMedPubMedCentral
26.
Taetle R, Rosen F, Abramson I, Venditti J, Howell S (1987) Use of nude mouse xenografts as preclinical drug screens: in vivo activity of established chemotherapeutic agents against melanoma and ovarian carcinoma xenografts. Cancer Treat Rep 71(3):297–304PubMed
27.
Chesney J, Clark J, Klarer AC, Imbert-Fernandez Y, Lane AN, Telang S (2014) 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 5(16):6670–6686CrossRefPubMedPubMedCentral
28.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat 123(3):725–731CrossRefPubMed
29.
Hudis CA (2007) Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med 357(1):39–51CrossRefPubMed
30.
31.
Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann oncol 19(9):1523–1529CrossRefPubMed
32.
Shojaei S, Gardaneh M, Shamabadi AR (2012) Target points in trastuzumab resistance. Intl J breast cancer 2012:761917CrossRef
33.
Almeida A, Bolanos JP, Moncada S (2010) E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation. Proc Natl Acad Sci U S A 107(2):738–741CrossRefPubMed
34.
Bando H, Atsumi T, Nishio T, Niwa H, Mishima S, Shimizu C, Yoshioka N, Bucala R, Koike T (2005) Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Clin Cancer Res 11(16):5784–5792CrossRefPubMed
35.
Zhao Y, Liu H, Liu Z, Ding Y, Ledoux SP, Wilson GL, Voellmy R, Lin Y, Lin W, Nahta R et al (2011) Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism. Cancer Res 71(13):4585–4597CrossRefPubMedPubMedCentral
36.
Clem BF, O’Neal J, Klarer AC, Telang S, Chesney J (2015) Clinical development of cancer therapeutics that target metabolism. QJM 109(6):367–372CrossRefPubMed
37.
Thornburg JM, Nelson KK, Clem BF, Lane AN, Arumugam S, Simmons A, Eaton JW, Telang S, Chesney J (2008) Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res 10(5):R84CrossRefPubMedPubMedCentral
Metadata
Title
Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2+ breast cancer
Authors
Julie O’Neal
Amy Clem
Lindsey Reynolds
Susan Dougherty
Yoannis Imbert-Fernandez
Sucheta Telang
Jason Chesney
Brian F. Clem
Publication date
01-11-2016
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2016
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-016-3968-8

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