Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin

Wang,Stephanie  S.; Hsiao,Ruth; Limpar,Mariko  M.; Lomahan,Sarah; Tran,Tuan-Anh; Maloney,Nolan  J.; Ikegaki,Naohiko; Tang,Xao   X.

doi:10.3892/ijmm.2013.1545

Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin

Authors:
- Stephanie S. Wang
- Ruth Hsiao
- Mariko M. Limpar
- Sarah Lomahan
- Tuan-Anh Tran
- Nolan J. Maloney
- Naohiko Ikegaki
- Xao X. Tang
View Affiliations

Affiliations: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
Published online on: November 1, 2013 https://doi.org/10.3892/ijmm.2013.1545
Pages: 35-42
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects.

View Figures

View References

1	Treuner J, Feine U, Niethammer D, Muller-Schaumburg W, Meinke J, Eibach E, Dopfer R, Klingebiel T and Grumbach S: Scintigraphic imaging of neuroblastoma with [131-I]iodobenzylguanidine. Lancet. 1:333–334. 1984.
2	Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng SC, Veatch J, Goldsby R, Brophy P, Kersun LS, Hawkins RA and Maris JM: Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 25:1054–1060. 2007. View Article : Google Scholar : PubMed/NCBI
3	Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY and Hammond D: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. New Engl J Med. 313:1111–1116. 1985. View Article : Google Scholar : PubMed/NCBI
4	Fredlund E, Ringner M, Maris JM and Pahlman S: High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci USA. 105:14094–14099. 2008. View Article : Google Scholar : PubMed/NCBI
5	Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K and Yamanaka S: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 131:861–872. 2007. View Article : Google Scholar
6	Ikegaki N, Shimada H, Fox AM, Regan PL, Jacobs JR, Hicks SL, Rappaport EF and Tang XX: Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas. Proc Natl Acad Sci USA. 110:6097–6102. 2013. View Article : Google Scholar : PubMed/NCBI
7	Ikegaki N, Regan PL, Hicks SL, Maloney N and Tang XX: Regulation of MYCN stability by reactive oxygen species in neuroblastoma. Cancer Res. 71(Suppl 1): Abstract LB-142. 2011. View Article : Google Scholar
8	Tang XX, Zhao H, Robinson ME, Cohen B, Cnaan A, London W, Cohn SL, Cheung NK, Brodeur GM, Evans AE and Ikegaki N: Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma. Proc Natl Acad Sci USA. 97:10936–10941. 2000. View Article : Google Scholar : PubMed/NCBI
9	Ikegaki N, Gotoh T, Kung B, Riceberg JS, Kim DY, Zhao H, Rappaport EF, Hicks SL, Seeger RC and Tang XX: De novo identification of MIZ-1 (ZBTB17) encoding a MYC-interacting zinc-finger protein as a new favorable neuroblastoma gene. Clin Cancer Res. 13:6001–6009. 2007. View Article : Google Scholar : PubMed/NCBI
10	Combaret V, Gross N, Lasset C, Frappaz D, Peruisseau G, Philip T, Beck D and Favrot MC: Clinical relevance of CD44 cell-surface expression and N-myc gene amplification in a multicentric analysis of 121 pediatric neuroblastomas. J Clin Oncol. 14:25–34. 1996.PubMed/NCBI
11	Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG, Cantor AB and Brodeur GM: Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med. 328:847–854. 1993. View Article : Google Scholar : PubMed/NCBI
12	Kogner P, Barbany G, Dominici C, Castello MA, Raschella G and Persson H: Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis. Cancer Res. 53:2044–2050. 1993.PubMed/NCBI
13	Suzuki T, Bogenmann E, Shimada H, Stram D and Seeger RC: Lack of high-affinity nerve growth factor receptors in aggressive neuroblastomas. J Nat Cancer Inst. 85:377–384. 1993. View Article : Google Scholar : PubMed/NCBI
14	Tang XX, Robinson ME, Riceberg JS, Kim DY, Kung B, Titus TB, Hayashi S, Flake AW, Carpentieri D and Ikegaki N: Favorable neuroblastoma genes and molecular therapeutics of neuroblastoma. Clin Cancer Res. 10:5837–5844. 2004. View Article : Google Scholar : PubMed/NCBI
15	Ikegaki N, Bukovsky J and Kennett RH: Identification and characterization of the NMYC gene product in human neuroblastoma cells by monoclonal antibodies with defined specificities. Proc Natl Acad Sci USA. 83:5929–5933. 1986. View Article : Google Scholar : PubMed/NCBI
16	Smets LA, Bout B and Wisse J: Cytotoxic and antitumor effects of the norepinephrine analogue meta-iodo-benzylguanidine (MIBG). Cancer Chemother Pharmacol. 21:9–13. 1988. View Article : Google Scholar : PubMed/NCBI
17	Kung B, Zhao H, Hicks SL, Tang XX and Ikegaki N: Biological significance of EPHA2 expression in neuroblastoma. Int J Oncol. 35:845–850. 2009.
18	Schlessinger A, Geier E, Fan H, Irwin JJ, Shoichet BK, Giacomini KM and Sali A: Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. Proc Natl Acad Sci USA. 108:15810–15815. 2011. View Article : Google Scholar : PubMed/NCBI
19	Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B and Gandini S: Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 3:1451–1461. 2010. View Article : Google Scholar : PubMed/NCBI
20	Bodmer M, Meier C, Krahenbuhl S, Jick SS and Meier CR: Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 33:1304–1308. 2010. View Article : Google Scholar : PubMed/NCBI
21	Wright JL and Stanford JL: Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control. 20:1617–1622. 2009. View Article : Google Scholar : PubMed/NCBI
22	Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ and Moller DE: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 108:1167–1174. 2001. View Article : Google Scholar : PubMed/NCBI
23	Warburg OH: Über den Stoffwechsel der Tumoren. Springer; Berlin: 1926
24	Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F and Viollet B: Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 120:2355–2369. 2010. View Article : Google Scholar : PubMed/NCBI
25	Shackelford DB and Shaw RJ: The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 9:563–575. 2009. View Article : Google Scholar : PubMed/NCBI
26	Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S and Bost F: Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 71:4366–4372. 2011.PubMed/NCBI
27	Weinhouse S: The Warburg hypothesis fifty years later. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol. 87:115–126. 1976.PubMed/NCBI
28	Dang CV: Therapeutic targeting of Myc-reprogrammed cancer cell metabolism. Cold Spring Harb Symp Quant Biol. 76:369–374. 2011. View Article : Google Scholar : PubMed/NCBI
29	Sweeney D, Raymer ML and Lockwood TD: Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents. Biochem Pharmacol. 66:663–677. 2003. View Article : Google Scholar : PubMed/NCBI
30	Owen MR, Doran E and Halestrap AP: Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 348:607–614. 2000. View Article : Google Scholar : PubMed/NCBI