Overcoming cetuximab resistance in Ewing's sarcoma by inhibiting lactate dehydrogenase-A

Fu,Jiaxin; Jiang,Han; Wu,Chenxuan; Jiang,Yi; Xiao,Lianping; Tian,Yonggang

doi:10.3892/mmr.2016.5290

Overcoming cetuximab resistance in Ewing's sarcoma by inhibiting lactate dehydrogenase-A

Authors:
- Jiaxin Fu
- Han Jiang
- Chenxuan Wu
- Yi Jiang
- Lianping Xiao
- Yonggang Tian
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Affiliations: Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, P.R. China
Published online on: May 17, 2016 https://doi.org/10.3892/mmr.2016.5290
Pages: 995-1001

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Abstract

Ewing's sarcoma, the second most common type of malignant bone tumor, generally occurs in children and young adults. The current treatment of Ewing's sarcoma comprises systemic anti‑cancer chemotherapy with complete surgical resection. However, the majority of patients with Ewing's sarcoma develop resistance to chemotherapy. The present study revealed an oncogenic role of lactate dehydrogenase‑A (LDHA) in the resistance of Ewing's sarcoma to cetuximab. LDHA was shown to be upregulated at the protein and mRNA level in cetuximab‑resistant Ewing's sarcoma tissues and a cell line. In addition, a link between LDHA‑induced glycolysis and cetuximab resistance in Ewing's sarcoma cells was revealed. Of note, inhibition of LDHA by either small interfering RNA or LDHA inhibitor oxamate significantly re‑sensitized cetuximab‑resistant cells to cetuximab. Combined treatment with LDHA inhibitor and cetuximab synergistically reduced the viability of cetuximab-resistant cells through the suppression of LDHA. The present study revealed a novel mechanism of cetuximab resistance from the perspective of cancer‑cell metabolism and provided a sensitization approach, which may aid in the development of anti-chemoresistance strategies for the treatment of cetuximab-resistant Ewing's sarcoma.

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1	Iwamoto Y: Diagnosis and treatment of Ewing's sarcoma. Jpn J Clin Oncol. 37:79–89. 2007. View Article : Google Scholar : PubMed/NCBI
2	Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, et al: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 348:694–701. 2003. View Article : Google Scholar : PubMed/NCBI
3	Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, et al: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: Evaluation of combination ifosfamide and etoposide - a Children's cancer group and pediatric oncology group study. J Clin Oncol. 22:2873–2876. 2004. View Article : Google Scholar : PubMed/NCBI
4	Longtin R: Ewing sarcoma: A miracle drug waiting to happen? J Natl Cancer Inst. 95:1574–1576. 2003. View Article : Google Scholar : PubMed/NCBI
5	May WA, Grigoryan RS, Keshelava N, Cabral DJ, Christensen LL, Jenabi J, Ji L, Triche TJ, Lawlor ER and Reynolds CP: Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines. PLoS One. 8:e800602013. View Article : Google Scholar : PubMed/NCBI
6	Fodale V, Pierobon M, Liotta L and Petricoin E: Mechanism of cell adaptation: When and how do cancer cells develop chemoresistance? Cancer J. 17:89–95. 2011. View Article : Google Scholar : PubMed/NCBI
7	Iida K, Fukushi J, Matsumoto Y, et al: miR-125b develops chemo-resistance in Ewing sarcomaprimitive neuroectodermal tumor. Cancer Cell Int. 13:212013. View Article : Google Scholar
8	Bardelli A and Jänne PA: The road to resistance: EGFR mutation and cetuximab. Nat Med. 18:199–200. 2012. View Article : Google Scholar : PubMed/NCBI
9	Yewale C, Baradia D, Vhora I, Patil S and Misra A: Epidermal growth factor receptor targeting in cancer: A review of trends and strategies. Biomaterials. 34:8690–8707. 2013. View Article : Google Scholar : PubMed/NCBI
10	Red Brewer M, Yun CH, Lai D, Lemmon MA, Eck MJ and Pao W: Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proc Natl Acad Sci USA. 110:E3595–E3604. 2013. View Article : Google Scholar : PubMed/NCBI
11	Graham J, Muhsin M and Kirkpatrick P: Cetuximab. Nat Rev Drug Discov. 3:549–550. 2004. View Article : Google Scholar : PubMed/NCBI
12	Fantin VR, St-Pierre J and Leder P: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology and tumor maintenance. Cancer Cell. 6:425–434. 2006. View Article : Google Scholar
13	Maftouh M, Avan A, Sciarrillo R, Granchi C, Leon LG, Rani R, Funel N, Smid K, Honeywell R, Boggi U, et al: Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. Br J Cancer. 110:172–182. 2014. View Article : Google Scholar :
14	Lu H, Li X, Luo Z, Liu J and Fan Z: Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A. Mol Cancer Ther. 12:2187–2199. 2013. View Article : Google Scholar : PubMed/NCBI
15	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
16	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
17	Henderson SR, Guiliano D, Presneau N, McLean S, Frow R, Vujovic S, Anderson J, Sebire N, Whelan J, Athanasou N, et al: A molecular map of mesenchymal tumors. Genome Biol. 206:R762005. View Article : Google Scholar
18	Zhou M, Zhao Y, Ding Y, Liu H, Liu Z, Fodstad O, Riker AI, Kamarajugadda S, Lu J, Owen LB, et al: Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer. 9:332010. View Article : Google Scholar : PubMed/NCBI
19	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
20	Li X, Zhao H, Zhou X and Song L: Inhibition of lactate dehydrogenase A by microRNA-34a resensitizes colon cancer cells to 5-fluorouracil. Mol Med Rep. 11:577–582. 2015.