Differential glycolytic profile and Warburg effect in papillary thyroid carcinoma cell lines

Coelho,Raquel  Guimarães; Cazarin,Juliana  de Menezes; Cavalcanti de Albuquerque,João    Paulo Albuquerque; de Andrade,Bruno  Moulin; Carvalho,Denise   P.

doi:10.3892/or.2016.5142

Differential glycolytic profile and Warburg effect in papillary thyroid carcinoma cell lines

Authors:
- Raquel Guimarães Coelho
- Juliana de Menezes Cazarin
- João Paulo Albuquerque Cavalcanti de Albuquerque
- Bruno Moulin de Andrade
- Denise P. Carvalho
View Affiliations

Affiliations: Laboratory of Endocrine Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
Published online on: October 4, 2016 https://doi.org/10.3892/or.2016.5142
Pages: 3673-3681

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acceleration of glycolysis is a characteristic of neoplasia. Previous studies have shown that a metabolic shift occurs in many tumors and correlates with a negative prognosis. The present study aimed to investigate the glycolytic profile of thyroid carcinoma cell lines. We investigated glycolytic and oxidative parameters of two thyroid carcinoma papillary cell lines (BCPAP and TPC1) and the non-tumor cell line NTHY-ori. All carcinoma cell lines showed higher rates of glycolysis efficiency, when compared to NTHY-ori, as assessed by a higher rate of glucose consumption and lactate production. The BCPAP cell line presented higher rates of growth, as well as elevated intracellular ATP levels, compared to the TPC1 and NTHY-ori cells. We found that glycolysis and activities of pentose phosphate pathway (PPP) regulatory enzymes were significantly different among the carcinoma cell lines, particularly in the mitochondrial hexokinase (HK) activity which was higher in the BCPAP cells than that in the TPC1 cell line which showed a balanced distribution of HK activity between cytoplasmic and mitochondrial subcellular localizations. However, TPC1 had higher levels of glucose‑6-phosphate dehydrogenase activity, suggesting that the PPP is elevated in this cell type. Using high resolution respirometry, we observed that the Warburg effect was present in the BCPAP and TPC1 cells, characterized by low oxygen consumption and high reactive oxygen species production. Overall, these results indicate that both thyroid papillary carcinoma cell lines showed a glycolytic profile. Of note, BCPAP cells presented some relevant differences in cell metabolism compared to TPC1 cells, mainly related to higher mitochondrial-associated HK activity.

View Figures

View References

1	Davies L and Welch HG: Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 295:2164–2167. 2006. View Article : Google Scholar : PubMed/NCBI
2	Pilli T, Prasad KV, Jayarama S, Pacini F and Prabhakar BS: Potential utility and limitations of thyroid cancer cell lines as models for studying thyroid cancer. Thyroid. 19:1333–1342. 2009. View Article : Google Scholar : PubMed/NCBI
3	Pacini F, Cetani F, Miccoli P, Mancusi F, Ceccarelli C, Lippi F, Martino E and Pinchera A: Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg. 18:600–604. 1994. View Article : Google Scholar : PubMed/NCBI
4	Nikiforova MN and Nikiforov YE: Molecular genetics of thyroid cancer: Implications for diagnosis, treatment and prognosis. Expert Rev Mol Diagn. 8:83–95. 2008. View Article : Google Scholar : PubMed/NCBI
5	van Staveren WC, Solís DW, Delys L, Duprez L, Andry G, Franc B, Thomas G, Libert F, Dumont JE, Detours V, et al: Human thyroid tumor cell lines derived from different tumor types present a common dedifferentiated phenotype. Cancer Res. 67:8113–8120. 2007. View Article : Google Scholar : PubMed/NCBI
6	Andrade BM and Carvalho DP: Perspective of the AMP-activated kinase (AMPK) signaling pathway in thyroid cancer. Biosci Rep. 34:181–187. 2014. View Article : Google Scholar
7	Andrade BM, Cazarin J, Zancan P and Carvalho DP: AMP-activated protein kinase upregulates glucose uptake in thyroid PCCL3 cells independent of thyrotropin. Thyroid. 22:1063–1068. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE and Fagin JA: High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 63:1454–1457. 2003.PubMed/NCBI
9	Xing M: BRAF mutation in thyroid cancer. Endocr Relat Cancer. 12:245–262. 2005. View Article : Google Scholar : PubMed/NCBI
10	Nikiforov YE and Nikiforova MN: Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 7:569–580. 2011. View Article : Google Scholar : PubMed/NCBI
11	Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 13:184–199. 2013. View Article : Google Scholar : PubMed/NCBI
12	Bläser D, Maschauer S, Kuwert T and Prante O: In vitro studies on the signal transduction of thyroidal uptake of ¹⁸F-FDG and ¹³¹I–Iodide. J Nucl Med. 47:1382–1388. 2006.PubMed/NCBI
13	Gatenby RA and Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 4:891–899. 2004. View Article : Google Scholar : PubMed/NCBI
14	Warburg O: On respiratory impairment in cancer cells. Science. 124:269–270. 1956.PubMed/NCBI
15	Gonzalez MJ, Massari JR Miranda, Duconge J, Riordan NH, Ichim T, Quintero-Del-Rio AI and Ortiz N: The bio-energetic theory of carcinogenesis. Med Hypotheses. 79:433–439. 2012. View Article : Google Scholar : PubMed/NCBI
16	Zhao Y, Butler EB and Tan M: Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 4:e5322013. View Article : Google Scholar : PubMed/NCBI
17	Amoêdo ND, Valencia JP, Rodrigues MF, Galina A and Rumjanek FD: How does the metabolism of tumor cells differ from that of normal cells. Biosci Rep. 33:e000802013.doi: 10.1042/BSR20130066. View Article : Google Scholar : PubMed/NCBI
18	Heiden MG Vander, Cantley LC and Thompson CB: Under-standing the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
19	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–1108. 2008. View Article : Google Scholar : PubMed/NCBI
20	Coelho RG, Calaça IC, Celestrini DM, Correia AH, Costa MA and Sola-Penna M: Clotrimazole disrupts glycolysis in human breast cancer without affecting non-tumoral tissues. Mol Genet Metab. 103:394–398. 2011. View Article : Google Scholar : PubMed/NCBI
21	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
22	Moreno-Sánchez R, Marín-Hernández A, Saavedra E, Pardo JP, Ralph SJ and Rodríguez-Enríquez S: Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. Int J Biochem Cell Biol. 50:10–23. 2014. View Article : Google Scholar : PubMed/NCBI
23	Soga T: Cancer metabolism: Key players in metabolic reprogramming. Cancer Sci. 104:275–281. 2013. View Article : Google Scholar : PubMed/NCBI
24	Vaupel P and Mayer A: Availability, not respiratory capacity governs oxygen consumption of solid tumors. Int J Biochem Cell Biol. 44:1477–1481. 2012. View Article : Google Scholar : PubMed/NCBI
25	Chen EI, Hewel J, Krueger JS, Tiraby C, Weber MR, Kralli A, Becker K, Yates JR III and Felding-Habermann B: Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res. 67:1472–1486. 2007. View Article : Google Scholar : PubMed/NCBI
26	Chen JQ and Russo J: Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta. 1826:370–384. 2012.PubMed/NCBI
27	Arciuch VG Antico, Russo MA, Kang KS and Di Cristofano A: Inhibition of AMPK and Krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells. Cancer Res. 73:5459–5472. 2013. View Article : Google Scholar : PubMed/NCBI
28	Dodson M, Darley-Usmar V and Zhang J: Cellular metabolic and autophagic pathways: Traffic control by redox signaling. Free Radic Biol Med. 63:207–221. 2013. View Article : Google Scholar : PubMed/NCBI
29	Stankov K, Biondi A, D'Aurelio M, Gasparre G, Falasca A, Romeo G and Lenaz G: Mitochondrial activities of a cell line derived from thyroid Hürthle cell tumors. Thyroid. 16:325–331. 2006. View Article : Google Scholar : PubMed/NCBI
30	Mathupala SP, Ko YH and Pedersen PL: Hexokinase-2 bound to mitochondria: Cancer's stygian link to the ‘Warburg effect’ and a pivotal target for effective therapy. Semin Cancer Biol. 19:17–24. 2009. View Article : Google Scholar : PubMed/NCBI
31	Ros S and Schulze A: Glycolysis back in the limelight: Systemic targeting of HK2 blocks tumor growth. Cancer Discov. 3:1105–1107. 2013. View Article : Google Scholar : PubMed/NCBI
32	Pastorino JG, Shulga N and Hoek JB: Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem. 277:7610–7618. 2002. View Article : Google Scholar : PubMed/NCBI
33	Marini C, Salani B, Massollo M, Amaro A, Esposito AI, Orengo AM, Capitanio S, Emionite L, Riondato M, Bottoni G, et al: Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer. Cell Cycle. 12:3490–3499. 2013. View Article : Google Scholar : PubMed/NCBI
34	Wilson JE: Isozymes of mammalian hexokinase: Structure, subcellular localization and metabolic function. J Exp Biol. 206:2049–2057. 2003. View Article : Google Scholar : PubMed/NCBI
35	Mazurek S: Pyruvate kinase type M2: a key regulator within the tumour metabolome and a tool for metabolic profiling of tumours. Ernst Schering Found Symp Proc. 2007:99–124. 2007.
36	Vidal AP, Andrade BM, Vaisman F, Cazarin J, Pinto LF, Breitenbach MM, Corbo R, Caroli-Bottino A, Soares F, Vaisman M, et al: AMP-activated protein kinase signaling is upregulated in papillary thyroid cancer. Eur J Endocrinol. 169:521–528. 2013. View Article : Google Scholar : PubMed/NCBI
37	Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, et al: AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17:113–124. 2013. View Article : Google Scholar : PubMed/NCBI
38	Cazarin JM, Coelho RG, Hecht F, Andrade BM and Carvalho DP: 5′-AMP-activated protein kinase regulates papillary (TPC-1 and BCPAP) thyroid cancer cell survival, migration, invasion, and epithelial-to-mesenchymal transition. Thyroid. 26:933–942. 2016. View Article : Google Scholar : PubMed/NCBI