Platelet isoform of phosphofructokinase promotes aerobic glycolysis and the progression of non‑small cell lung cancer

Wang,Fuan; Li,Ling; Zhang,Zhen

doi:10.3892/mmr.2020.11712

Platelet isoform of phosphofructokinase promotes aerobic glycolysis and the progression of non‑small cell lung cancer

Authors:
- Fuan Wang
- Ling Li
- Zhen Zhang
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Affiliations: Department of Surgical Group, Medical College of Pingdingshan University, Pingdingshan, Henan 467000, P.R. China, Department of Respiratory Medicine, First People's Hospital of Jinan, Jinan, Shandong 250000, P.R. China, Department of Neurosurgery, Shandong Provincial Hospital, Jinan, Shandong 250012, P.R. China
Published online on: November 20, 2020 https://doi.org/10.3892/mmr.2020.11712
Article Number: 74
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The platelet isoform of phosphofructokinase (PFKP) is a rate‑limiting enzyme involved in glycolysis that serves an important role in various types of cancer. The aim of the present study was to explore the specific regulatory relationship between PFKP and non‑small cell lung cancer (NSCLC) progression. PFKP expression in NSCLC tissues and corresponding adjacent tissues was detected using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemical analysis. PFKP expression in human bronchial epithelial cells (16HBE) and NSCLC cells (H1299, H23 and A549) was also detected using RT‑qPCR. Cell proliferation was detected by Cell Counting Kit‑8 and colony formation assays. Transwell invasion and wound healing assays, and flow cytometry were used to detect cell invasion, migration and apoptosis, respectively. The expression levels of glycolysis‑associated enzymes (hexokinase‑2, lactate dehydrogenase A and glucose transporter‑1), epithelial‑mesenchymal transition‑related proteins (N‑cadherin, vimentin and E‑cadherin) and apoptosis‑related proteins (caspase‑3 and B‑cell lymphoma‑2) were detected by western blotting. Glucose uptake, lactate production and the adenosine trisphosphate/adenosine diphosphate ratio were measured using the corresponding kits. The results of the present study demonstrated that PFKP expression was upregulated in NSCLC tissues and cells, and PFKP expression was related to lymph node metastasis and histological grade. In addition, overexpression of PFKP inhibited cell apoptosis, and promoted proliferation, migration, invasion and glycolysis of H1299 cells, whereas knockdown of PFKP had the opposite effects. In conclusion, PFKP inhibited cell apoptosis, and promoted proliferation, migration, invasion and glycolysis of NSCLC cells; these findings may lay the foundation for novel treatments of NSCLC.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Walker S: Updates in non-small cell lung cancer. Clin J Oncol Nurs. 12:587–596. 2008. View Article : Google Scholar : PubMed/NCBI
3	Shao Y, Liang B, Long L and Jiang SJ: Diagnostic MicroRNA biomarker discovery for non-small-cell lung cancer adenocarcinoma by integrative bioinformatics analysis. Biomed Res Int. 2017:25630852017. View Article : Google Scholar : PubMed/NCBI
4	Wu C, Zhu W, Qian J, He S, Wu C, Chen Y and Shu Y: WT1 promotes invasion of NSCLC via suppression of CDH1. J Thorac Oncol. 8:1163–1169. 2013. View Article : Google Scholar : PubMed/NCBI
5	De Mukherjee K, Vats A, Ghosh D and Pillai SK: Data analysis and network study of non-small-cell lung cancer biomarkers. Advances in Computational Intelligence. Sahana S and Bhattacharjee V: Springer; Singapore: pp. 265–272. 2020, View Article : Google Scholar
6	Liao Y, Cao L, Wang F and Pang R: miR-605-5p promotes invasion and proliferation by targeting TNFAIP3 in non-small-cell lung cancer. J Cell Biochem. 121:779–787. 2020. View Article : Google Scholar : PubMed/NCBI
7	Li Z, Li X, Wu S, Xue M and Chen W: Long non-coding RNA UCA1 promotes glycolysis by upregulating hexokinase 2 through the mTOR-STAT3/microRNA143 pathway. Cancer Sci. 105:951–955. 2014. View Article : Google Scholar : PubMed/NCBI
8	Liu X, Wang X, Zhang J, Lam EK, Shin VY, Cheng AS, Yu J, Chan FK, Sung JJ and Jin HC: Warburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis. Oncogene. 29:442–450. 2010. View Article : Google Scholar : PubMed/NCBI
9	Meienhofer Mc, De Medicis E, Cognet M and Kahn A: Regulation of genes for glycolytic enzymes in cultured rat hepatoma cell lines. Eur J Biochem. 169:237–243. 1987. View Article : Google Scholar : PubMed/NCBI
10	Brand K: Aerobic glycolysis by proliferating Cells: Protection against oxidative stress at the expense of energy yield. J Bioenerg Biomembr. 29:355–364. 1997. View Article : Google Scholar : PubMed/NCBI
11	Gillies RJ, Robey I and Gatenby RA: Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 49 (Suppl 2):24S–42S. 2008. View Article : Google Scholar : PubMed/NCBI
12	Lang N, Wang C, Zhao J, Shi F, Wu T and Cao H: Long non-coding RNA BCYRN1 promotes glycolysis and tumor progression by regulating the miR-149/PKM2 axis in non-small-cell lung cancer. Mol Med Rep. 21:1509–1516. 2020.PubMed/NCBI
13	Gan J, Li S, Meng Y, Liao Y, Jiang M, Qi L, Li Y and Bai Y: The influence of photodynamic therapy on the Warburg effect in esophageal cancer cells. Lasers Med Sci. 35:1741–1750. 2020. View Article : Google Scholar : PubMed/NCBI
14	Li J, Cheng D, Zhu M, Yu H, Pan Z, Liu L, Geng Q, Pan H, Yan M and Yao M: OTUB2 stabilizes U2AF2 to promote the Warburg effect and tumorigenesis via the AKT/mTOR signaling pathway in non-small cell lung cancer. Theranostics. 9:179–195. 2019. View Article : Google Scholar : PubMed/NCBI
15	Shi J, Wang H, Feng W, Huang S, An J, Qiu Y and Wu K: MicroRNA-130a targeting hypoxia-inducible factor 1 alpha suppresses cell metastasis and Warburg effect of NSCLC cells under hypoxia. Life Sci. 255:1178262020. View Article : Google Scholar : PubMed/NCBI
16	Liu T and Yin H: PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer. Oncol Rep. 37:193–200. 2017. View Article : Google Scholar : PubMed/NCBI
17	Park YY, Kim SB, Han HD, Sohn BH, Kim JH, Liang J, Lu Y, Rodriguez-Aguayo C, Lopez-Berestein G, Mills GB, et al: Tat-activating regulatory DNA-binding protein regulates glycolysis in hepatocellular carcinoma by regulating the platelet isoform of phosphofructokinase through microRNA 520. Hepatology. 58:182–191. 2013. View Article : Google Scholar : PubMed/NCBI
18	Zhang YM, Liu JK and Wong TY: The DNA excision repair system of the highly radioresistant bacterium Deinococcus radiodurans is facilitated by the pentose phosphate pathway. Mol Microbiol. 48:1317–1323. 2003. View Article : Google Scholar : PubMed/NCBI
19	Chen Y, Xu Q, Ji D, Wei Y, Chen H, Li T, Wan B, Yuan L, Huang R and Chen G: Inhibition of pentose phosphate pathway suppresses acute myelogenous leukemia. Tumour Biol. 37:6027–6034. 2016. View Article : Google Scholar : PubMed/NCBI
20	Kim NH, Cha YH, Lee J, Lee SH, Yang JH, Yun JS, Cho ES, Zhang X, Nam M, Kim N, et al: Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress. Nat Commun. 8:143742017. View Article : Google Scholar : PubMed/NCBI
21	Wang J, Zhang P, Zhong J, Tan M, Ge J, Tao L, Li Y, Zhu Y, Wu L, Qiu J and Tong X: The platelet isoform of phosphofructokinase contributes to metabolic reprogramming and maintains cell proliferation in clear cell renal cell carcinoma. Oncotarget. 7:27142–27157. 2016. View Article : Google Scholar : PubMed/NCBI
22	Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV, et al: An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 173:400–416.e11. 2018. View Article : Google Scholar : PubMed/NCBI
23	Love MI, Huber W and Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15:5502014. View Article : Google Scholar : PubMed/NCBI
24	Therneau T M and Grambsch P M: Modeling Survival Data: Extending the Cox Model. Springer; New York, NY: 2000, View Article : Google Scholar
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Reck M, Heigener DF, Mok T, Soria JC and Rabe KF: Management of non-small-cell lung cancer: Recent developments. Lancet. 382:709–719. 2013. View Article : Google Scholar : PubMed/NCBI
27	Mor I, Cheung EC and Vousden KH: Control of glycolysis through regulation of PFK1: Old friends and recent additions. Cold Spring Harb Symp Quant Biol. 76:211–216. 2011. View Article : Google Scholar : PubMed/NCBI
28	Wang C, Chen S, Wang Y, Liu X, Hu F, Sun J and Yuan H: Lipase-triggered water-responsive ‘Pandora's Box’ for cancer therapy: Toward induced neighboring effect and enhanced drug penetration. Adv Mater. 30:e17064072018. View Article : Google Scholar : PubMed/NCBI
29	Tang D, Zhao X, Zhang L, Wang Z and Wang C: Identification of hub genes to regulate breast cancer metastasis to brain by bioinformatics analyses. J Cell Biochem. 120:9522–9531. 2019. View Article : Google Scholar : PubMed/NCBI
30	Lee JH, Liu R, Li J, Zhang C, Wang Y, Cai Q, Qian X, Xia Y, Zheng Y, Piao Y, et al: Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun. 8:9492017. View Article : Google Scholar : PubMed/NCBI
31	Chen G, Liu H, Zhang Y, Liang J, Zhu Y, Zhang M, Yu D, Wang C and Hou J: Silencing PFKP inhibits starvation-induced autophagy, glycolysis, and epithelial mesenchymal transition in oral squamous cell carcinoma. Exp Cell Res. 370:46–57. 2018. View Article : Google Scholar : PubMed/NCBI
32	Wegener G and Krause U: Different modes of activating phosphofructokinase, a key regulatory enzyme of glycolysis, in working vertebrate muscle. Biochem Soc Trans. 30:264–270. 2002. View Article : Google Scholar : PubMed/NCBI
33	Moon JS, Kim HE, Koh E, Park SH, Jin WJ, Park BW, Park SW and Kim KS: Krüppel-like factor 4 (KLF4) activates the transcription of the gene for the platelet isoform of phosphofructokinase (PFKP) in breast cancer. J Biol Chem. 286:23808–23816. 2011. View Article : Google Scholar : PubMed/NCBI
34	Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA III, Peters EC, Driggers EM and Hsieh-Wilson LC: Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 337:975–980. 2012. View Article : Google Scholar : PubMed/NCBI
35	Yang J, Li J, Le Y, Zhou C, Zhang S and Gong Z: PFKL/miR-128 axis regulates glycolysis by inhibiting AKT phosphorylation and predicts poor survival in lung cancer. Am J Cancer Res. 6:473–485. 2016.PubMed/NCBI
36	Tam WL and Weinberg RA: The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 19:1438–1449. 2013. View Article : Google Scholar : PubMed/NCBI
37	Zhou P, Li B, Liu F, Zhang M, Wang Q, Liu Y, Yao Y and Li D: The epithelial to mesenchymal transition (EMT) and cancer stem cells: Implication for treatment resistance in pancreatic cancer. Mol Cancer. 16:522017. View Article : Google Scholar : PubMed/NCBI
38	Ma P, Tang WG, Hu JW, Hao Y, Xiong LK, Wang M, Liu H, Bo WH and Yu KH: HSP4 triggers epithelial-mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT. Liver Int. 40:1211–1223. 2020. View Article : Google Scholar : PubMed/NCBI
39	Xiao Y, Xie Q, Qin Q, Liang Y, Lin H and Zeng D: Upregulation of SOX11 enhances tamoxifen resistance and promotes epithelial-to-mesenchymal transition via slug in MCF-7 breast cancer cells. J Cell Physiol. 235:7295–7308. 2020. View Article : Google Scholar : PubMed/NCBI
40	Yang L, Yu Y, Xiong Z, Chen H, Tan B and Hu H: Downregulation of SEMA4C inhibit epithelial-mesenchymal transition (EMT) and the invasion and metastasis of cervical cancer cells via inhibiting transforming growth factor-beta 1 (TGF-β1)-induced hela cells p38 mitogen-activated protein kinase (MAPK) activation. Med Sci Monit. 26:e9181232020. View Article : Google Scholar : PubMed/NCBI
41	Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC, Lu Z, et al: ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 14:1295–1304. 2012. View Article : Google Scholar : PubMed/NCBI
42	Liu L, Wang Y, Bai R, Yang K and Tian Z: MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation. Oncogenesis. 6:e3182017. View Article : Google Scholar : PubMed/NCBI
43	Akram M: Mini-review on glycolysis and cancer. J Cancer Educ. 28:454–457. 2013. View Article : Google Scholar : PubMed/NCBI
44	Ganapathy-Kanniappan S: Molecular intricacies of aerobic glycolysis in cancer: Current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol. 53:667–682. 2018. View Article : Google Scholar : PubMed/NCBI
45	Wan W, Peng K, Li M, Qin L, Tong Z, Yan J, Shen B and Yu C: Histone demethylase JMJD1A promotes urinary bladder cancer progression by enhancing glycolysis through coactivation of hypoxia inducible factor 1α. Oncogene. 36:3868–3877. 2017. View Article : Google Scholar : PubMed/NCBI
46	Xu H, Zeng Y, Liu L, Gao Q, Jin S, Lan Q, Lai W, Luo X, Wu H, Huang Y and Chu Z: PRL-3 improves colorectal cancer cell proliferation and invasion through IL-8 mediated glycolysis metabolism. Int J Oncol. 51:1271–1279. 2017. View Article : Google Scholar : PubMed/NCBI