Effect of PTEN loss on metabolic reprogramming in prostate cancer cells

Zhou,Xin; Yang,Xu; Sun,Xiang; Xu,Xinyuan; Li,Xi'an; Guo,Yan; Wang,Jiancai; Li,Xia; Yao,Libo; Wang,He; Shen,Lan

doi:10.3892/ol.2019.9932

Effect of PTEN loss on metabolic reprogramming in prostate cancer cells

Authors:
- Xin Zhou
- Xu Yang
- Xiang Sun
- Xinyuan Xu
- Xi'an Li
- Yan Guo
- Jiancai Wang
- Xia Li
- Libo Yao
- He Wang
- Lan Shen
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Affiliations: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: January 14, 2019 https://doi.org/10.3892/ol.2019.9932
Pages: 2856-2866
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The tumor suppressor gene PTEN is one of the most often deleted genes in human prostate cancer. Loss of PTEN is an important event in prostate carcinogenesis. Metabolic reprogramming induced by PTEN loss fuels malignant growth and proliferation of prostate cancer cells. Targeted metabolomics analysis was used to investigate the effects of PTEN loss on intracellular metabolic pathways in prostate cancer cells. DU‑145 cells were transfected with PTEN siRNAs (siRNA‑1 and siRNA‑2) for 48 h, and endogenous PTEN expression was monitored by western blotting. Changes in intracellular metabolites were determined by liquid chromatography‑tandem mass chromatography (LC‑MS/MS) and gas chromatography‑mass spectrometry (GC‑MS). Most intracellular metabolites involved in glycolysis and glutaminolysis were increased in PTEN knockdown prostate cancer cells. In addition, most intracellular metabolites involved in fatty acid de novo synthesis, fatty acid beta oxidation and branched chain amino acid catabolism were also increased in PTEN knockdown prostate cancer cells. These results revealed that PTEN loss induced the metabolic reprogramming of prostate cancer cells and promoted the malignant proliferation of prostate cancer cells. The present metabolomics analysis indicates that tumor suppressor gene PTEN mutation or deletion can induce metabolic reprogramming in prostate cancer cells and tumorigenesis by altering the metabolic flux of glycolysis, glutaminolysis, fatty acid metabolism and branched chain amino acid catabolism pathways. Metabolic reprogramming is one of the contributors to PTEN‑loss driven prostate cancer.

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1	Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, et al: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 275:1943–1947. 1997. View Article : Google Scholar : PubMed/NCBI
2	Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, Thomas GV, Li G, Roy-Burman P, Nelson PS, et al: Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 4:209–221. 2003. View Article : Google Scholar : PubMed/NCBI
3	Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, Xue Q, Bikoff R, Ma H, Kantoff PW, Golub TR, et al: Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model. Proc Natl Acad Sci USA. 100:7841–7846. 2003. View Article : Google Scholar : PubMed/NCBI
4	Chang CJ, Mulholland DJ, Valamehr B, Mosessian S, Sellers WR and Wu H: PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression. Mol Cell Biol. 28:3281–3289. 2008. View Article : Google Scholar : PubMed/NCBI
5	Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, et al: PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell. 3:117–130. 2003. View Article : Google Scholar : PubMed/NCBI
6	Vivanco I, Palaskas N, Tran C, Finn SP, Getz G, Kennedy NJ, Jiao J, Rose J, Xie W, Loda M, et al: Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell. 11:555–569. 2007. View Article : Google Scholar : PubMed/NCBI
7	Warburg O: On respiratory impairment in cancer cells. Science. 124:269–270. 1956.PubMed/NCBI
8	Schlaepfer IR, Rider L, Rodrigues LU, Gijón MA, Pac CT, Romero L, Cimic A, Sirintrapun SJ, Glodé LM, Eckel RH and Cramer SD: Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol Cancer Ther. 13:2361–2371. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wu X, Daniels G, Lee P and Monaco ME: Lipid metabolism in prostate cancer. Am J Clin Exp Urol. 2:111–120. 2014.PubMed/NCBI
10	Van de Sande T, De Schrijver E, Heyns W, Verhoeven G and Swinnen JV: Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Res. 62:642–646. 2002.PubMed/NCBI
11	Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, de Boer VC, Anastasiou D, Ito K, Sasaki AT, Rameh L, et al: Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell. 149:49–62. 2012. View Article : Google Scholar : PubMed/NCBI
12	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
13	Hsu PP and Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell. 134:703–707. 2008. View Article : Google Scholar : PubMed/NCBI
14	Kroemer G and Pouyssegur J: Tumor cell metabolism: Cancer's Achilles' heel. Cancer Cell. 13:472–482. 2008. View Article : Google Scholar : PubMed/NCBI
15	Shen L, Sun X, Fu Z, Yang G, Li J and Yao L: The fundamental role of the p53 pathway in tumor metabolism and its implication in tumor therapy. Clin Cancer Res. 18:1561–1567. 2012. View Article : Google Scholar : PubMed/NCBI
16	Toren P, Kim S, Johnson F and Zoubeidi A: Combined AKT and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer. PLoS One. 11:e01528612016. View Article : Google Scholar : PubMed/NCBI
17	Wang L, Xiong H, Wu F, Zhang Y, Wang J, Zhao L, Guo X, Chang LJ, Zhang Y, You MJ, et al: Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 8:1461–1474. 2014. View Article : Google Scholar : PubMed/NCBI
18	Kwabi-Addo B, Giri D, Schmidt K, Podsypanina K, Parsons R, Greenberg N and Ittmann M: Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci USA. 98:11563–11568. 2001. View Article : Google Scholar : PubMed/NCBI
19	Fraser M, Zhao H, Luoto KR, Lundin C, Coackley C, Chan N, Joshua AM, Bismar TA, Evans A, Helleday T and Bristow RG: PTEN deletion in prostate cancer cells does not associate with loss of RAD51 function: Implications for radiotherapy and chemotherapy. Clin Cancer Res. 18:1015–1027. 2012. View Article : Google Scholar : PubMed/NCBI
20	Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, Pleier SV, Bai AHC, Karra D, Piro RM, et al: BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med. 19:901–908. 2013. View Article : Google Scholar : PubMed/NCBI
21	Billingsley KL, Park JM, Josan S, Hurd R, Mayer D, Spielman-Sun E, Nishimura DG, Brooks JD and Spielman D: The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate. Magn Reson Imaging. 32:791–795. 2014. View Article : Google Scholar : PubMed/NCBI
22	Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, Cheng L, Masterson TA, Liu X, Ratliff TL and Cheng JX: Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 19:393–406. 2014. View Article : Google Scholar : PubMed/NCBI
23	Cordero-Espinoza L and Hagen T: Increased concentrations of fructose 2,6-bisphosphate contribute to the Warburg effect in phosphatase and tensin homolog (PTEN)-deficient cells. J Biol Chem. 288:36020–36028. 2013. View Article : Google Scholar : PubMed/NCBI
24	Moon JS, Jin WJ, Kwak JH, Kim HJ, Yun MJ, Kim JW, Park SW and Kim KS: Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells. Biochem J. 433:225–233. 2011. View Article : Google Scholar : PubMed/NCBI
25	Phadngam S, Castiglioni A, Ferraresi A, Morani F, Follo C and Isidoro C: PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells. Oncotarget. 7:84999–85020. 2016. View Article : Google Scholar : PubMed/NCBI
26	Butler LM, Centenera MM and Swinnen JV: Androgen control of lipid metabolism in prostate cancer: Novel insights and future applications. Endocr Relat Cancer. 23:R219–R227. 2016. View Article : Google Scholar : PubMed/NCBI
27	Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, et al: Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 113:1774–1783. 2004. View Article : Google Scholar : PubMed/NCBI
28	Chen J, Guccini I, Di Mitri D, Brina D, Revandkar A, Sarti M, Pasquini E, Alajati A, Pinton S, Losa M, et al: Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat Genet. 50:219–228. 2018. View Article : Google Scholar : PubMed/NCBI
29	Zhou W, Feng X, Ren C, Jiang X, Liu W, Huang W, Liu Z, Li Z, Zeng L, Wang L, et al: Over-expression of BCAT1, a c-Myc target gene, induces cell proliferation, migration and invasion in nasopharyngeal carcinoma. Mol Cancer. 12:532013. View Article : Google Scholar : PubMed/NCBI
30	Zhu W, Shao Y and Peng Y: MicroRNA-218 inhibits tumor growth and increases chemosensitivity to CDDP treatment by targeting BCAT1 in prostate cancer. Mol Carcinog. 56:1570–1577. 2017. View Article : Google Scholar : PubMed/NCBI