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01-12-2020 | osteosarcoma | Primary research

Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect through reactive oxygen species in osteosarcoma

Published in: Cancer Cell International | Issue 1/2020

Abstract

Background

Iron metabolism disorder is closely associated with several malignant tumors, however the mechanisms underlying iron and the carcinogenesis in osteosarcoma are not yet well understood.

Methods

Cell proliferation ability of osteosarcoma cell lines was measured by CCK-8, EdU incorporation and colony formation assays. Cell cycle analysis was detected by flow cytometry. The carcinogenesis of osteosarcoma was measured by soft-agar formation, trans-well and Wound healing-scratch assay. Warburg effect was detected by Seahorse respirometry assays. Reactive oxygen species (ROS) level was measured by Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probes. Western blotting was used to measure the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28). Iron level in vitro and vivo was detected by iron assay kit. RNAi stable cell lines was generated using shRNA.

Results

Iron promoted proliferation, carcinogenesis and Warburg effect of osteosarcoma cells. Iron-induced reactive oxygen species (ROS) played an important role in these processes. Iron accumulated more in mitochondrion than in cytoplasm, suggesting mitochondrion-mediated iron accumulation was involved in the development of osteosarcoma. Moreover, iron upregulated the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28). Knock-down of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28) decreased the production of ROS. In addition, iron increased the expression of Warburg key enzymes HK2 and Glut1, and affected AMPK/mTORC1 signaling axis.

Conclusions

Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect of osteosarcoma cells. Meanwhile, iron deprivation might be a novel effective strategy in the treatment of osteosarcoma.

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Arredondo M, Núñez MT. Iron and copper metabolism. Mol Aspects Med. 2005;26(4–5):313–27.PubMedCrossRef

Heath JL, Weiss JM, Lavau CP, Wechsler DS. Iron deprivation in cancer–potential therapeutic implications. Nutrients. 2013;5(8):2836–59.PubMedPubMedCentralCrossRef

Nairz M, Schroll A, Demetz E, Tancevski I, Theurl I, Weiss G. ‘Ride on the ferrous wheel’–the cycle of iron in macrophages in health and disease. Immunobiology. 2015;220(2):280–94.PubMedCrossRef

Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142(1):24–38.PubMedCrossRef

Bach FH. Heme oxygenase-1: a therapeutic amplification funnel. FASEB J. 2005;19(10):1216–9.PubMedCrossRef

Gozzelino R, Andrade BB, Larsen R, et al. Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe. 2012;12(5):693–704.PubMedCrossRef

Lill R. Function and biogenesis of iron-sulphur proteins. Nature. 2009;460(7257):831–8.PubMedCrossRef

Paradkar PN, Zumbrennen KB, Paw BH, Ward DM, Kaplan J. Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol Cell Biol. 2009;29(4):1007–16.PubMedCrossRef

Ichikawa Y, Ghanefar M, Bayeva M, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest. 2014;124(2):617–30.PubMedPubMedCentralCrossRef

10.

Haddad S, Wang Y, Galy B, et al. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J. 2017;38(5):362–72.PubMed

11.

Cloonan SM, Glass K, Laucho-Contreras ME, et al. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med. 2016;22(2):163–74.PubMedPubMedCentralCrossRef

12.

Zacharski LR, Chow BK, Howes PS, et al. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst. 2008;100(14):996.PubMedCrossRef

13.

Osborne NJ, Gurrin LC, Allen KJ, et al. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology. 2010;51(4):1311–8.PubMedCrossRef

14.

Torti SV, Manz DH, Paul BT, Blanchette-Farra N, Torti FM. Iron and Cancer. Annu Rev Nutr. 2018;38:97–125.PubMedCrossRef

15.

Nelson RL. Iron and colorectal cancer risk: human studies. Nutr Rev. 2001;59(5):140–8.PubMedCrossRef

16.

Xue X, Taylor M, Anderson E, et al. Hypoxia-inducible factor-2α activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 2012;72(9):2285–93.PubMedPubMedCentralCrossRef

17.

Kuang Y, Wang Q. Iron and lung cancer. Cancer Lett. 2019;464:56–61.PubMedCrossRef

18.

Xue X, Ramakrishnan SK, Weisz K, et al. Iron uptake via DMT1 integrates cell cycle with JAK-STAT3 signaling to promote colorectal tumorigenesis. Cell Metab. 2016;24(3):447–61.PubMedPubMedCentralCrossRef

19.

Kuang Y, Guo W, Ling J, et al. Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130/STAT3 signaling pathway. Cell Death Dis. 2019;10(4):297.PubMedPubMedCentralCrossRef

20.

Seril DN, Liao J, Yang G-Y, Yang CS. Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis. 2003;24(3):353–62.PubMedCrossRef

21.

Li C, Zhang Y, Cheng X, et al. PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev Cell. 2018;46(4):441.PubMedCrossRef

22.

Li P, Zheng X, Shou K, et al. The iron chelator Dp44mT suppresses osteosarcoma’s proliferation, invasion and migration: in vitro and in vivo. Am J Transl Res. 2016;8(12):5370–85.PubMedPubMedCentral

23.

Shang C, Zhou H, Liu W, Shen T, Luo Y, Huang S. Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways. Oncogene. 2020;39(29):5201–13.PubMedPubMedCentralCrossRef

24.

Agnihotri S, Golbourn B, Huang X, et al. PINK1 is a negative regulator of growth and the Warburg effect in glioblastoma. Cancer Res. 2016;76(16):4708–19.PubMedCrossRef

25.

Teng R, Liu Z, Tang H, et al. HSP60 silencing promotes Warburg-like phenotypes and switches the mitochondrial function from ATP production to biosynthesis in ccRCC cells. Redox Biol. 2019;24:101218.PubMedPubMedCentralCrossRef

26.

Hart PC, Mao M, de Abreu ALP, et al. MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat Commun. 2015;6:6053.PubMedPubMedCentralCrossRef

27.

Alessio N, Aprile D, Squillaro T, et al. The senescence-associated secretory phenotype (SASP) from mesenchymal stromal cells impairs growth of immortalized prostate cells but has no effect on metastatic prostatic cancer cells. Aging. 2019;11(15):5817–28.PubMedPubMedCentralCrossRef

28.

Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13(5):342–55.PubMedPubMedCentralCrossRef

29.

Finicelli M, Benedetti G, Squillaro T, et al. Expression of stemness genes in primary breast cancer tissues: the role of SOX2 as a prognostic marker for detection of early recurrence. Oncotarget. 2014;5(20):9678–88.PubMedPubMedCentralCrossRef

30.

Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf). 2009;196(1):65–80.CrossRef

31.

Kong Y, Hu L, Lu K, et al. Ferroportin downregulation promotes cell proliferation by modulating the Nrf2-miR-17-5p axis in multiple myeloma. Cell Death Dis. 2019;10(9):624.PubMedPubMedCentralCrossRef

32.

Rodic S, Vincent MD. Reactive oxygen species (ROS) are a key determinant of cancer’s metabolic phenotype. Int J Cancer. 2018;142(3):440–8.PubMedCrossRef

33.

Turrens JF. Superoxide production by the mitochondrial respiratory chain. Biosci Rep. 1997;17(1):3–8.PubMedCrossRef

34.

Guo W, Kuang Y, Wu J, et al. Hexokinase 2 depletion confers sensitization to metformin and inhibits glycolysis in lung squamous cell carcinoma. Front Oncol. 2020;10:52.PubMedPubMedCentralCrossRef

35.

Momcilovic M, Bailey ST, Lee JT, et al. The GSK3 signaling axis regulates adaptive glutamine metabolism in lung squamous cell carcinoma. Cancer Cell. 2018;33(5):905–21.PubMedPubMedCentralCrossRef

Title: Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect through reactive oxygen species in osteosarcoma
Publication date: 01-12-2020
Keywords: osteosarcoma
Osteosarcoma
Published in: Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-020-01494-3

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Abstract

Background

Methods

Results

Conclusions

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