Combination of 3PO analog PFK15 and siPFKL efficiently suppresses the migration, colony formation ability, and PFK-1 activity of triple-negative breast cancers by reducing the glycolysis.
PFK15
PFKFB3. PFKP
PFKL
TNBC
aerobic glycolysis
Journal
Journal of cellular biochemistry
ISSN: 1097-4644
Titre abrégé: J Cell Biochem
Pays: United States
ID NLM: 8205768
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
14
04
2023
received:
15
10
2022
accepted:
05
07
2023
medline:
22
9
2023
pubmed:
14
7
2023
entrez:
14
7
2023
Statut:
ppublish
Résumé
Among all the subtypes of breast cancer, triple-negative breast cancer (TNBC) has been associated with the worst prognosis. Recently, for many solid tumors (including breast cancer) metabolic reprogramming has appeared as a cancer cell hallmark, and the elevated glycolytic pathway has been linked to their aggressive phenotype. In the present study, we evaluated the prognostic and therapeutic relevance of PFKFB3 (6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase) in TNBCs. Prognostic significance of PFKFB3 expression was evaluated in overall breast cancers as well as in TNBCs. PFKFB3 inhibitor (3PO potent analogue i.e., PFK15) cytotoxicity in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was analyzed using an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cancer cell physiological characteristics like clonogenicity and migration were also investigated after PFK15 treatment. As fructose-2,6-bisphosphate (F-2,6-BP), has been associated with increased PFK-1 activity, the effect of PFKFB3 inhibition by PFK15 was investigated on two major isoforms of phosphofructokinase-1 (PFK-1) in breast cancer, that is, phosphofructokinase-platelet type (PFKP) and phosphofructokinase-liver type (PFKL) (relevant to breast cancer). For PFKL inhibition, the siRNA approach was used. PFKFB3 expression was significantly correlated with inferior overall survival in breast cancer patients including TNBCs. PFK15 treatment in TNBC cells (i.e., MDA-MB-231 and MDA-MB-468) resulted in a decreased PFKP expression, thereby leading to reduced colony formation ability, migration rate, and extracellular lactate levels. However, to our surprise PFK15 treatment in both TNBC cells also resulted in elevated PFKL levels. Our results demonstrated that the combinatorial inhibition of PFK15 with siPFKL was more effective in TNBC cells, as it led to a decrease in colony formation ability, migration rate, extracellular lactate levels, and PFK-1 activity when compared with individual treatments. Using bona fide PFKFB3 inhibitor, that is, AZ67, we further show that AZ67 treatment to TNBC cells has no effect either on the expression of PFKP and PFKL, or on the lactate production. In summary, our present in vitro study demonstrated that 3PO derived PFK15 mechanism of action is totally different from AZ67 in TNBC cells. However, we advocate that the PFK15-mediated inhibition (along with PFKL) on the TNBCs migration, colony formation, and PFK-1 activity can be further explored for the therapeutic advantage of TNBC patients.
Substances chimiques
PFK15
0
Phosphofructokinase-2
EC 2.7.1.105
Lactates
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1259-1272Informations de copyright
© 2023 Wiley Periodicals LLC.
Références
Boyle P. Triple-negative breast cancer: epidemiological considerations and recommendations. Ann Oncol. 2012;23(6):vi7-vi12.
Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry. Cancer. 2007;109(9):1721-1728.
Bianchini G, De Angelis C, Licata L, Gianni L. Treatment landscape of triple-negative breast cancer-expanded options, evolving needs. Nat Rev Clin Oncol. 2022;19(2):91-113.
Sandhu GS, Erqou S, Patterson H, Mathew A. Prevalence of triple-negative breast cancer in India: systematic review and meta-analysis. J Glob Oncol. 2016;2(6):412-421.
Kulkarni A, Kelkar DA, Parikh N, Shashidhara LS, Koppiker CB, Kulkarni M. Meta-analysis of prevalence of triple-negative breast cancer and its clinical features at incidence in Indian patients with breast cancer. JCO Glob Oncol. 2020;6:1052-1062.
Akhtar M, Dasgupta S, Rangwala M. Triple negative breast cancer: an Indian perspective. Breast Cancer (Dove Med Press). 2015;7:239-243.
Samec M, Liskova A, Koklesova L, et al. Flavonoids against the Warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism. EPMA J. 2020;11(3):377-398.
Annibaldi A, Widmann C. Glucose metabolism in cancer cells. Curr Opin Clin Nutr Metab Care. 2010;13(4):466-470.
Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441-464.
Liberti MV, Locasale JW. The warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41(3):211-218.
Villa E, Ali E, Sahu U, Ben-Sahra I. Cancer cells tune the signaling pathways to empower de novo synthesis of nucleotides. Cancers. 2019;11(5):688.
Arundhathi JRD, Mathur SR, Gogia A, Deo SVS, Mohapatra P, Prasad CP. Metabolic changes in triple negative breast cancer-focus on aerobic glycolysis. Mol Biol Rep. 2021;48(5):4733-4745.
Bartrons R, Simon-Molas H, Rodríguez-García A, et al. Fructose 2,6-Bisphosphate in cancer cell metabolism. Front Oncol. 2018;8:331.
Houddane A, Bultot L, Novellasdemunt L, et al. Role of Akt/PKB and PFKFB isoenzymes in the control of glycolysis, cell proliferation and protein synthesis in mitogen-stimulated thymocytes. Cell Signal. 2017;34:23-37.
Kocemba KA, Dulińska-Litewka J, Wojdyła KL, Pękala 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(0):938-950.
Minchenko O, Opentanova I, Caro J. Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family (PFKFB-1-4) expression in vivo. FEBS Lett. 2003;554(3):264-270.
Obach M, Navarro-Sabaté À, Caro J, et al. 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia. J Biol Chem. 2004;279(51):53562-53570.
Atsumi T, Chesney J, Metz C, et al. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 2002;62(20):5881-5887.
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):945-954.
Minchenko OH. Mechanisms of regulation of PFKFB expression in pancreatic and gastric cancer cells. World J Gastroenterol. 2014;20(38):13705-13717.
Clem BF, O'Neal J, Tapolsky G, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther. 2013;12(8):1461-1470.
Emini Veseli B, Perrotta P, Van Wielendaele P, et al. Small molecule 3PO inhibits glycolysis but does not bind to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). FEBS Lett. 2020;594(18):3067-3075.
Boyd S, Brookfield JL, Critchlow SE, et al. Structure-based design of potent and selective inhibitors of the metabolic kinase PFKFB3. J Med Chem. 2015;58(8):3611-3625.
Györffy B, Lanczky A, Eklund AC, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725-731.
Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 1987;47:936-942.
Bartha Á, Győrffy B. TNMplot.com: aweb tool for the comparison of gene expression in normal, tumor and metastatic tissues. Int J Mol Sci. 2021;22(5):2622.
Heiser LM, Sadanandam A, Kuo WL, et al. Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc Natl Acad Sci USA. 2012;109:2724-2729.
Wang G, Xu Z, Wang C, et al. Differential phosphofructokinase-1 isoenzyme patterns associated with glycolytic efficiency in human breast cancer and paracancer tissues. Oncol Lett. 2013;6(6):1701-1706.
Prasad CP, Södergren K, Andersson T. Reduced production and uptake of lactate are essential for the ability of WNT5A signaling to inhibit breast cancer cell migration and invasion. Oncotarget. 2017;8(42):71471-71488.
Umar SM, Kashyap A, Kahol S, et al. Prognostic and therapeutic relevance of phosphofructokinase platelet-type (PFKP) in breast cancer. Exp Cell Res. 2020;396(1):112282.
Yeerken D, Hong R, Wang Y, et al. PFKP is transcriptionally repressed by BRCA1/ZBRK1 and predicts prognosis in breast cancer. PLoS One. 2020;15(5):e0233750.
Li N, Wang X, Sun J, et al. miR-21-5p/Tiam1-mediated glycolysis reprogramming drives breast cancer progression via enhancing PFKL stabilization. Carcinogenesis. 2022;43:705-715. doi:10.1093/carcin/bgac039
Cheung RA, Kraft AM, Petty HR. Relocation of phosphofructokinases within epithelial cells is a novel event preceding breast cancer recurrence that accurately predicts patient outcomes. Am J Physiol Cell Physiol. 2021;321(4):C654-C670.
Zhang X, Wang J, Zhuang J, et al. A novel glycolysis-related four-mRNA signature for predicting the survival of patients with breast cancer. Front Genet. 2021;12:606937.
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519-530.
Shi L, Pan H, Liu Z, Xie J, Han W. Roles of PFKFB3 in cancer. Signal Transduct Target Ther. 2017;2:17044.
Kim BG, Sung JS, Jang Y, et al. Compression-induced expression of glycolysis genes in CAFs correlates with EMT and angiogenesis gene expression in breast cancer. Commun Biol. 2019;2:313.
Huang J, Yang M, Liu Z, et al. PPFIA4 promotes colon cancer cell proliferation and migration by enhancing tumor glycolysis. Front Oncol. 2021;11:653200.
Lei L, Hong LL, Ling ZN, et al. A potential oncogenic role for PFKFB3 overexpression in gastric cancer progression. Clin Transl Gastroenterol. 2021;12(7):e00377.
Xing J, Jia Z, Xu Y, et al. KLF9 (Kruppel Like Factor 9) induced PFKFB3 (6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3) downregulation inhibits the proliferation, metastasis and aerobic glycolysis of cutaneous squamous cell carcinoma cells. Bioengineered. 2021;12(1):7563-7576.
Novellasdemunt L, Obach M, Millán-Ariño L, et al. Progestins activate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells. Biochem J. 2012;442(2):345-356.
Ge X, Lyu P, Cao Z, et al. Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting. Biochem Biophys Res Commun. 2015;463(4):1115-1121.
La Belle Flynn A, Calhoun BC, Sharma A, Chang JC, Almasan A, Schiemann WP. Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression. Nat Commun. 2019;10(1):3668.
Li HM, Yang JG, Liu ZJ, et al. 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.
Yang J, Li J, Le Y, Zhou C, Zhang S, Gong Z. PFKL/miR-128 axis regulates glycolysis by inhibiting AKT phosphorylation and predicts poor survival in lung cancer. Am J Cancer Res. 2016;6(2):473-485.
Feng Y, Zhang Y, Cai Y, et al. A20 targets PFKL and glycolysis to inhibit the progression of hepatocellular carcinoma. Cell Death Dis. 2020;11(2):89.
Zheng C, Yu X, Liang Y, et al. Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner. Acta Pharm Sin B. 2022;12(3):1271-1287.
Burmistrova O, Olias-Arjona A, Lapresa R, et al. Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice. Sci Rep. 2019;9(1):11670.
Emini Veseli B, Van Wielendaele P, Delibegovic M, Martinet W, De Meyer GRY. The PFKFB3 inhibitor AZ67 inhibits angiogenesis independently of glycolysis inhibition. Int J Mol Sci. 2021;22(11):5970.