Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Neuroblastoma | Hypothesis

The influence of PFK-II overexpression on neuroblastoma patients’ survival may be dependent on the particular isoenzyme expressed, PFKFB3 or PFKFB4

Authors: Sonia E. Trojan, Michał J. Markiewicz, Katarzyna Leśkiewicz, Kinga A. Kocemba-Pilarczyk

Published in: Cancer Cell International | Issue 1/2019

Login to get access

Abstract

Background/Aim

During cancer progression metabolic reprogramming is observed in parallel to the alternation in transcriptional profiles of malignant cells. Recent studies suggest that metabolic isoenzymes of phosphofructokinase II (PFK-II) – PFKFB3 and PFKFB4, often induced in hypoxic environment, significantly contribute to enhancement of glucose metabolism and in consequence cancer progression.

Materials and methods

Using the publicly available data deposited in the R2 data base we performed a Kaplan–Meyer analysis for cancer patients divided into groups with high and low expression levels of PFKFB3/4, determined based on the median.

Results

Our data showed that high PFKFB3/4 expression significantly correlates with shorter overall survival in several cancers. Moreover, we found that neuroblastoma patients with poor overall survival and evidence free survival are characterized by high PFKFB3 and at the same time low PFKFB4 expression, whereas patients with high PFKFB4 expressions are characterized by significantly better overall survival/evidence free survival rates.

Conclusion

Our analysis clearly indicates that expression of PFKFB3/4 isoenzymes may have a key prognostic value for several cancers. What’s more, it seems that in neuroblastoma the prognostic value of PFK-II may be dependent on the relation between PFKFB3 and PFKFB4 isoenzyme expression, indicating that further studies analyzing the role of both cancer specific PFK-II isoenzymes are highly desired.
Literature
1.
Warburg O. Über den Stoffwechsel der Carcinomzelle. Naturwissenschaften. 1924;12(50):1131–7.CrossRef
2.
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519–30.CrossRef
3.
Yu L, Chen X, Sun X, Wang L, Chen S. The glycolytic switch in tumors: how many players are involved? J Cancer. 2017;8(17):3430–40.CrossRef
4.
DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200.PubMed
5.
Yi M, Ban Y, Tan Y, Xiong W, Li G, Xiang B. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: a pair of valves for fine-tuning of glucose metabolism in human cancer. Mol Metab. 2019;20:1–13.CrossRef
6.
Shi L, Pan H, Liu Z, Xie J, Han W. Roles of PFKFB3 in cancer. Signal Transduct Target Ther. 2017;2:17044.CrossRef
7.
Kocemba KA, Dulinska-Litewka J, Wojdyla KL, Pekala PA. The role of 6-phosphofructo-2-kinase (PFK-2)/fructose 2,6-bisphosphatase (FBPase-2) in metabolic reprogramming of cancer cells. Postepy Hig Med Dosw (Online). 2016;70:938–50.CrossRef
8.
Li HM, Yang JG, Liu ZJ, Wang WM, Yu ZL, Ren JG, Chen G, Zhang W, Jia J. Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma. J Exp Clin Cancer Res. 2017;36(1):7.CrossRef
9.
O’Neal J, Clem A, Reynolds L, Dougherty S, Imbert-Fernandez Y, Telang S, Chesney J, Clem BF. Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2 + breast cancer. Breast Cancer Res Treat. 2016;160(1):29–40.CrossRef
10.
Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, et al. Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell. 2016;30(6):968–85.CrossRef
11.
Chesney J, Clark J, Lanceta L, Trent JO, Telang S. Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor. Oncotarget. 2015;6(20):18001–11.CrossRef
12.
Taylor C, Mannion D, Miranda F, Karaminejadranjbar M, Herrero-Gonzalez S, Hellner K, Zheng Y, Bartholomeusz G, Bast RC Jr, Ahmed AA. Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells. Oncotarget. 2017;8(11):17960–80.CrossRef
13.
Dasgupta S, Rajapakshe K, Zhu B, Nikolai BC, Yi P, Putluri N, Choi JM, Jung SY, Coarfa C, Westbrook TF, et al. Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 2018;556(7700):249–54.CrossRef
14.
Jia W, Zhao X, Zhao L, Yan H, Li J, Yang H, Huang G, Liu J. Non-canonical roles of PFKFB3 in regulation of cell cycle through binding to CDK4. Oncogene. 2018;37(13):1685–98.CrossRef
15.
Yan S, Wei X, Xu S, Sun H, Wang W, Liu L, Jiang X, Zhang Y, Che Y. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 spatially mediates autophagy through the AMPK signaling pathway. Oncotarget. 2017;8(46):80909–22.CrossRef
16.
Yalcin A, Clem BF, Imbert-Fernandez Y, Ozcan SC, Peker S, O’Neal J, Klarer AC, Clem AL, Telang S, Chesney J. 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. Cell Death Dis. 2014;5:e1337.CrossRef
17.
18.
Edgar R, Domrachev M, Lash AE. Gene Expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–10.CrossRef
19.
Trojan SE, Piwowar M, Ostrowska B, Laidler P, Kocemba-Pilarczyk KA. Analysis of malignant melanoma cell lines exposed to hypoxia reveals the importance of PFKFB4 overexpression for disease progression. Anticancer Res. 2018;38(12):6745–52.CrossRef
20.
Yao L, Wang L, Cao ZG, Hu X, Shao ZM. High expression of metabolic enzyme PFKFB4 is associated with poor prognosis of operable breast cancer. Cancer Cell Int. 2019;19:165.CrossRef
21.
Peng F, Li Q, Sun JY, Luo Y, Chen M, Bao Y. PFKFB3 is involved in breast cancer proliferation, migration, invasion and angiogenesis. Int J Oncol. 2018;52(3):945–54.PubMed
22.
Li X, Liu J, Qian L, Ke H, Yao C, Tian W, Liu Y, Zhang J. Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy. Mol Cell Biochem. 2018;445(1–2):123–34.CrossRef
23.
Goidts V, Bageritz J, Puccio L, Nakata S, Zapatka M, Barbus S, Toedt G, Campos B, Korshunov A, Momma S, et al. RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene. 2012;31(27):3235–43.CrossRef
24.
Shi WK, Zhu XD, Wang CH, Zhang YY, Cai H, Li XL, Cao MQ, Zhang SZ, Li KS, Sun HC. PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT. Cell Death Dis. 2018;9(4):428.CrossRef
25.
Yun SJ, Jo SW, Ha YS, Lee OJ, Kim WT, Kim YJ, Lee SC, Kim WJ. PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer. Urol Oncol. 2012;30(6):893–9.CrossRef
26.
Kim SG, Manes NP, El-Maghrabi MR, Lee YH. Crystal structure of the hypoxia-inducible form of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3): a possible new target for cancer therapy. J Biol Chem. 2006;281(5):2939–44.CrossRef
27.
Sakakibara R, Kato M, Okamura N, Nakagawa T, Komada Y, Tominaga N, Shimojo M, Fukasawa M. Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase. J Biochem. 1997;122(1):122–8.CrossRef
28.
Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J. 2004;381(Pt 3):561–79.CrossRef
29.
Almeida A, Bolanos JP, Moncada S. E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation. Proc Natl Acad Sci U S A. 2010;107(2):738–41.CrossRef
30.
Lu Z, Hunter T. Metabolic kinases moonlighting as protein kinases. Trends Biochem Sci. 2018;43(4):301–10.CrossRef
31.
Klarer AC, O’Neal J, Imbert-Fernandez Y, Clem A, Ellis SR, Clark J, Clem B, Chesney J, Telang S. Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism. Cancer Metab. 2014;2(1):2.CrossRef
32.
Yalcin A, Clem BF, Simmons A, Lane A, Nelson K, Clem AL, Brock E, Siow D, Wattenberg B, Telang S, et al. Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases. J Biol Chem. 2009;284(36):24223–32.CrossRef
Metadata
Title
The influence of PFK-II overexpression on neuroblastoma patients’ survival may be dependent on the particular isoenzyme expressed, PFKFB3 or PFKFB4
Authors
Sonia E. Trojan
Michał J. Markiewicz
Katarzyna Leśkiewicz
Kinga A. Kocemba-Pilarczyk
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-1005-9

Other articles of this Issue 1/2019

Cancer Cell International 1/2019 Go to the issue

Primary research

Long noncoding RNA DLX6-AS1 promotes neuroblastoma progression by regulating miR-107/BDNF pathway

Primary research

Clinical-biological characteristics and treatment outcomes of pediatric pro-B ALL patients enrolled in BCH-2003 and CCLG-2008 protocol: a study of 121 Chinese children

Primary research

Low-dose zoledronate for the treatment of bone metastasis secondary to prostate cancer

Primary research

hsa_circ_0081143 promotes cisplatin resistance in gastric cancer by targeting miR-646/CDK6 pathway

Primary research

Prognostic significance of platelet-to-lymphocyte ratio in urothelial carcinoma patients: a meta-analysis

Primary research

Alpha-mangostin induces endoplasmic reticulum stress and autophagy which count against fatty acid synthase inhibition mediated apoptosis in human breast cancer cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits