Iron metabolism disturbances in the MCF-7 human breast cancer cells with acquired resistance to doxorubicin and cisplatin

Chekhun,Vasyl  F.; Lukyanova,Natalia  Yu.; Burlaka,Аnatoliy  P.; Bezdenezhnykh,Natalia  A.; Shpyleva,Svitlana  I.; Tryndyak,Volodymyr  P.; Beland,Frederick  A.; Pogribny,Igor  P.

doi:10.3892/ijo.2013.2063

Iron metabolism disturbances in the MCF-7 human breast cancer cells with acquired resistance to doxorubicin and cisplatin

Authors:
- Vasyl F. Chekhun
- Natalia Yu. Lukyanova
- Аnatoliy P. Burlaka
- Natalia A. Bezdenezhnykh
- Svitlana I. Shpyleva
- Volodymyr P. Tryndyak
- Frederick A. Beland
- Igor P. Pogribny
View Affiliations

Affiliations: Department of Mechanisms of Anticancer Therapy, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Kiev, Ukraine, Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA
Published online on: August 20, 2013 https://doi.org/10.3892/ijo.2013.2063
Pages: 1481-1486

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

The development of resistance of cancer cells to therapeutic agents is the major obstacle in the succesful treatment of breast cancer and the main cause of breast cancer recurrence. The results of several studies have demonstrated an important role of altered cellular iron metabolism in the progression of breast cancer and suggested that iron metabolism may be involved in the acquisition of a cancer cell drug-resistant phenotype. In the present study, we show that human MCF-7 breast cancer cells with an acquired resistance to the chemotherapeutic drugs doxorubicin (MCF-7/DOX) and cisplatin (MCF-7/CDDP) exhibited substantial alterations in the intracellular iron content and levels of iron-regulatory proteins involved in the cellular uptake, storage and export of iron, especially in profoundly increased levels of ferritin light chain (FTL) protein. The increased levels of FTL in breast cancer indicate that FTL may be used as a diagnostic and prognostic marker for breast cancer. Additionally, we demonstrate that targeted downregulation of FTL protein by the microRNA miR-133a increases sensitivity of MCF-7/DOX and MCF-7/CDDP cells to doxorubicin and cisplatin. These results suggest that correction of iron metabolism abnormalities may substantially improve the efficiency of breast cancer treatment.

View Figures

View References

1.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2011. View Article : Google Scholar
2.	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
3.	Gonzalez-Angulo AM, Morales-Vasquez F and Hortobagyi GN: Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol. 608:1–22. 2007. View Article : Google Scholar : PubMed/NCBI
4.	Pinnix ZK, Miller LD, Wang W, D’Agostino R Jr, Kute T, Willingham MC, Hatcher H, Tesfay L, Sui G, Di X, Torti SV and Torti FM: Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med. 2:43ra562010. View Article : Google Scholar : PubMed/NCBI
5.	Torti SV and Torti FM: Ironing out cancer. Cancer Res. 71:1511–1514. 2011. View Article : Google Scholar : PubMed/NCBI
6.	Miller LD, Cofman LG, Chou JW, Black MA, Bergh J, D’Agostino R Jr, Torti SV and Torti FM: An iron gene signature predicts outcome in breast cancer. Cancer Res. 71:6728–6737. 2011. View Article : Google Scholar : PubMed/NCBI
7.	Kwok JC and Richardson DR: The iron metabolism of neoplastic cells: alterations that facilitate proliferation? Crit Rev Oncol Hematol. 42:65–78. 2002. View Article : Google Scholar : PubMed/NCBI
8.	Yu Y, Gutierrez E, Kovacevic Z, Saletta F, Obeidy P, Rahmanto YS and Richardson DR: Iron chelators for the treatment of cancer. Curr Med Chem. 19:2689–2702. 2012. View Article : Google Scholar : PubMed/NCBI
9.	Hoke EM, Maylock CA and Shacter E: Desferal inhibits tumor growth and does not interfere with tumoricidal activity of doxorubicin. Free Radic Biol Med. 39:403–411. 2005. View Article : Google Scholar : PubMed/NCBI
10.	Rao VA, Klein SR, Agama KK, Toyoda E, Adaci N, Pommier Y and Shacter EB: The iron chelator Dp44mT causes DNA damage and selective inhibition of topoisomerase II alpha in breast cancer cells. Cancer Res. 69:948–957. 2009. View Article : Google Scholar : PubMed/NCBI
11.	Whitnall M, Howard J, Ponka P and Richardson DR: A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA. 103:14901–14906. 2006. View Article : Google Scholar : PubMed/NCBI
12.	Chekhun VF, Lukyanova NYu, Kovalchuk O, Tryndyak VP and Pogribny IP: Epigenetic profiling of multidrug-resistant human MCF-7 breast adenocarcinoma cells reveals novel hyper- and hypomethylated targets. Mol Cancer Ther. 6:1089–1098. 2007. View Article : Google Scholar
13.	Kars MD, Iseri OD, Gündüz U, Ural AU, Arpaci F and Molnár J: Development of rational in vitro models for drug resistance in breast cancer and modulation of MDR by selected compounds. Anticancer Res. 26:4559–4568. 2006.PubMed/NCBI
14.	Pate KT, Randel NA, Fraser B, Clement MH and Srinivasan C: Measuring ‘free’ iron levels in Caenorhabditis elegans using low-temperature Fe(III) electron paramagnetic resonance spectroscopy. Anal Biochem. 358:199–207. 2006.
15.	McClelland RA, Wilson D and Leake R: A multicentre study into the reliability of steroid receptor immunocytochemical assay quantification. Eur J Cancer. 27:711–715. 1991. View Article : Google Scholar : PubMed/NCBI
16.	Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S and Boyd MR: New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 82:1107–1112. 1990. View Article : Google Scholar : PubMed/NCBI
17.	Ni J and Hollander D: Application of the MTT-assay to functional studies of mouse intestinal intraepithelial lymphocytes. J Clin Lab Anal. 10:42–52. 1996. View Article : Google Scholar : PubMed/NCBI
18.	Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlard-Davenport A, Chekhun VF, Beland FA and Pogribny IP: Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat. 126:63–71. 2011. View Article : Google Scholar : PubMed/NCBI
19.	Arosio P, Ingrassia and Cavadini P: Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta. 1790:589–599. 2009. View Article : Google Scholar : PubMed/NCBI
20.	Dorr RT: Bleomycin pharmacology: mechanism of action and resistance and clinical pharmacokinetics. Semin Oncol. 19(Suppl 5): 3–8. 1992.PubMed/NCBI
21.	Wu Z, Wang C, Xiang R, Liu X, Ye S, Yang X, Zhang G, Xu X, Zhu T and Wu Q: Loss of miR133a expression is associated with poor survival of breast cancer and restoration of miR-133a expression inhibited breast cancer growth and invasion. BMC Cancer. 12:512012. View Article : Google Scholar : PubMed/NCBI
22.	Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, Chekhun VF and Pogribny IP: Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 7:2152–2159. 2008. View Article : Google Scholar : PubMed/NCBI
23.	Pogribny IP, Filkowski JN, Tryndyak VP, Golubov A, Shpyleva SI and Kovalchuk O: Alterations of microRNAs and their targets are associated with acquired resistance of MCF-7 breast cancer cells to cisplatin. Int J Cancer. 127:1785–1794. 2010. View Article : Google Scholar : PubMed/NCBI
24.	Kanojia D, Zhou W, Zhang J, Jie C, Lo PK, Wang Q and Chen H: Proteomic profiling of cancer stem cells from primary tumors of HER2/Neu transgenic mice. Proteomics. 12:3407–3415. 2012. View Article : Google Scholar : PubMed/NCBI
25.	Eswaran J, Cyanam D, Mudravi P, Reddy SD, Pakala SB, Nair SS, Florea L, Fuqua SA, Godbole S and Kumar R: Transcriptomic landscape of breast cancers through mRNA sequencing. Sci Rep. 2:2642012. View Article : Google Scholar : PubMed/NCBI
26.	Descotes F, Jézéquel P, Spyratos F, Campion L, Grenot C, Lerebours F, Campone M, Guérin-Charbonnel C, Lanoë D, Adams M, andré J, Carlioz A, Martin PM, Chassevent A, Jourdan ML, Guette C, Zanella-Cleon I and Ricolleau G: Identification of potential prognostic biomarkers for node-negative breast tumours by proteomic analysis: a multicentric 2004 national PHRC study. Int J Oncol. 41:92–104. 2012.PubMed/NCBI
27.	Dong X, Yang M, Sun H, Lü J, Zheng Z, Li Z and Zhong L: Combined measurement of CA 15-3 with novel autoantibodies improves diagnostic accuracy for breast cancer. Onco Targets Ther. 6:273–279. 2013.PubMed/NCBI
28.	Xu X, Persson HL and Richardson DR: Molecular pharmacology of the interaction of anthracyclines with iron. Mol Pharmacol. 68:261–271. 2005.PubMed/NCBI
29.	Xu X, Sutak R and Richardson DR: Iron chelation by clinically relevant anthracyclines: alteration in expression of iron-regulated genes and atypical changes in intracellular iron distribution and trafficking. Mol Pharmacol. 73:833–844. 2008. View Article : Google Scholar : PubMed/NCBI
30.	Canzoneri JC and Oyelere AK: Interaction of anthracyclines with iron responsive elements mRNAs. Nucleic Acids Res. 36:6825–6834. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Thompson KJ, Fried MG, Ye Z, Boyer P and Connor JR: Regulation, mechanisms and proposed function of ferritin trans-location to cell nuclei. J Cell Sci. 114:2165–2177. 2002.PubMed/NCBI
32.	Alkhateeb AA and Connor JR: Nuclear ferritin: a new role for ferritin in cell biology. Biochim Biophys Acta. 1800:793–797. 2010. View Article : Google Scholar : PubMed/NCBI
33.	Yang DC, Jiang X, Elliot RL and Head JF: Antisense ferritin oligonucleotides inhibit growth and induce apoptosis in human breast carcinoma cells. Anticancer Res. 22:1513–1524. 2002.
34.	Liu X, Madhankumar AB, Slagle-Webb B, Sheehan JM, Surguladze N and Connor JR: Heavy chain ferritin siRNA delivered by cationic liposomes increases sensitivity of cancer cells to chemotherapeutic agents. Cancer Res. 71:2240–2249. 2011. View Article : Google Scholar