Curcumin‑induced promoter hypermethylation of the mammalian target of rapamycin gene in multiple myeloma cells

Chen,Jiaqi; Ying,Yongli; Zhu,Hongjun; Zhu,Tingjun; Qu,Chunsheng; Jiang,Jinhong; Fang,Bingmu

doi:10.3892/ol.2018.9662

Curcumin‑induced promoter hypermethylation of the mammalian target of rapamycin gene in multiple myeloma cells

Authors:
- Jiaqi Chen
- Yongli Ying
- Hongjun Zhu
- Tingjun Zhu
- Chunsheng Qu
- Jinhong Jiang
- Bingmu Fang
View Affiliations

Affiliations: Clinical Laboratory, Lishui People's Hospital, Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China, Department of Surgery, Lishui People's Hospital, Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China, Department of Hematology, Lishui People's Hospital, Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
Published online on: November 5, 2018 https://doi.org/10.3892/ol.2018.9662
Pages: 1108-1114
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Curcumin, a polyphenol derived from the rhizome of Curcuma, is a potential tumor inhibitor through affecting signaling pathways and epigenetic regulation. The mammalian target of rapamycin (mTOR) gene serves a crucial role in the carcinogenesis of multiple myeloma. The curcumin‑induced epigenetic regulation of mTOR, including promoter DNA methylation in multiple myeloma, has not yet been fully elucidated. In the present study, antitumor effects of curcumin were investigated in RPMI‑8226 and NCI‑H929 cells using an MTT assay and flow cytometry. The expression of mTOR and DNA methyltransferase proteins were determined by western blot analysis, and the methylation status of the mTOR promoter were detected by sequencing following bisulfite conversion. The results of the present study revealed that the half‑maximal inhibitory concentration of curcumin was 10 µM in myeloma cells. Following curcumin treatment, the mRNA and protein expression levels of mTOR were decreased by 43.31 and 39.34% in NCI‑H929 cells, respectively. The promoter of mTOR, located in chromosome 1 (chromosome position, 11262153‑11263153), contains a CpG island that was hypermethylated in myeloma cells following curcumin treatment. The expression levels of DNA methyltransferase (DNMT)3a and DNMT3b were increased in curcumin‑treated cells. Collectively, these results indicate that curcumin serves a role in the epigenetic regulation of mTOR expression, and that mTOR downregulation is due to promoter hypermethylation, which may be associated with DNMT3a and DNMT3b upregulation. The results of the present study contribute towards improving the understanding of curcumin treatment in multiple myeloma and provide novel insights into the molecular mechanisms underlying the epigenetic regulation of mTOR.

View Figures

View References

1	Dimopoulos MA and Terpos E: Multiple myeloma. Ann Oncol. 21 Suppl 7:vii143–vii150. 2010. View Article : Google Scholar : PubMed/NCBI
2	Quach H, Prince HM and Spencer A: Managing multiple myeloma in the elderly: Are we making progress? Expert Rev Hematol. 4:301–315. 2011. View Article : Google Scholar : PubMed/NCBI
3	Mateos MV, Masszi T, Grzasko N, Hansson M, Sandhu I, Pour L, Viterbo L, Jackson SR, Stoppa AM, Gimsing P, et al: Impact of prior therapy on the efficacy and safety of oral ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in TOURMALINE-MM1. Haematologica. 102:1767–1775. 2017. View Article : Google Scholar : PubMed/NCBI
4	Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, et al: Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 374:1621–1634. 2016. View Article : Google Scholar : PubMed/NCBI
5	Howells LM, Mitra A and Manson MM: Comparison of oxaliplatin- and curcumin-mediated antiproliferative effects in colorectal cell lines. Int J Cancer. 121:175–183. 2007. View Article : Google Scholar : PubMed/NCBI
6	Jin G, Yang Y, Liu K, Zhao J, Chen X, Liu H, Bai R, Li X, Jiang Y, Zhang X, et al: Combination curcumin and (−)-epigallocatechin-3-gallate inhibits colorectal carcinoma microenvironment-induced angiogenesis by JAK/STAT3/IL-8 pathway. Oncogenesis. 6:e3842017. View Article : Google Scholar : PubMed/NCBI
7	Weissenberger J, Priester M, Bernreuther C, Rakel S, Glatzel M, Seifert V and Kögel D: Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin Cancer Res. 16:5781–5795. 2010. View Article : Google Scholar : PubMed/NCBI
8	Zanotto-Filho A, Braganhol E, Klafke K, Figueiró F, Terra SR, Paludo FJ, Morrone M, Bristot IJ, Battastini AM, Forcelini CM, et al: Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas. Cancer Lett. 358:220–231. 2015. View Article : Google Scholar : PubMed/NCBI
9	Ye M and Zhang J and Zhang J, Miao Q, Yao L and Zhang J: Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer. Cancer Lett. 357:196–205. 2015. View Article : Google Scholar : PubMed/NCBI
10	Srivastava RK, Chen Q, Siddiqui I, Sarva K and Shankar S: Linkage of curcumin-induced cell cycle arrest and apoptosis by cyclin-dependent kinase inhibitor p21(/WAF1/CIP1). Cell Cycle. 6:2953–2961. 2007. View Article : Google Scholar : PubMed/NCBI
11	Shinojima N, Yokoyama T, Kondo Y and Kondo S: Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 3:635–637. 2007. View Article : Google Scholar : PubMed/NCBI
12	Cao P, Maira SM, García-Echeverría C and Hedley DW: Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer. 100:1267–1276. 2009. View Article : Google Scholar : PubMed/NCBI
13	Nassim R, Mansure JJ, Chevalier S, Cury F and Kassouf W: Combining mTOR inhibition with radiation improves antitumor activity in bladder cancer cells in vitro and in vivo: A novel strategy for treatment. PLoS One. 8:e652572013. View Article : Google Scholar : PubMed/NCBI
14	Tasian SK, Teachey DT, Li Y, Shen F, Harvey RC, Chen IM, Ryan T, Vincent TL, Willman CL, Perl AE, et al: Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 129:177–187. 2017. View Article : Google Scholar : PubMed/NCBI
15	Zoncu R, Efeyan A and Sabatini DM: mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 12:21–35. 2011. View Article : Google Scholar : PubMed/NCBI
16	Suangtamai T and Tanyong DI: Diallyl disulfide induces apoptosis and autophagy via mTOR pathway in myeloid leukemic cell line. Tumour Biol. 37:10993–10999. 2016. View Article : Google Scholar : PubMed/NCBI
17	Wang FM, Galson DL, Roodman GD and Ouyang H: Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells. Exp Hematol. 39:999–1006. 2011. View Article : Google Scholar : PubMed/NCBI
18	Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U and Kundu TK: Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 279:51163–51171. 2004. View Article : Google Scholar : PubMed/NCBI
19	Kang J, Chen J, Shi Y, Jia J and Zhang Y: Curcumin-induced histone hypoacetylation: The role of reactive oxygen species. Biochem Pharmacol. 69:1205–1213. 2005. View Article : Google Scholar : PubMed/NCBI
20	Kang SK, Cha SH and Jeon HG: Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev. 15:165–174. 2006. View Article : Google Scholar : PubMed/NCBI
21	Liu Z, Xie Z, Jones W, Pavlovicz RE, Liu S, Yu J, Li PK, Lin J, Fuchs JR, Marcucci G, et al: Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706–709. 2009. View Article : Google Scholar : PubMed/NCBI
22	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 : PubMed/NCBI
23	Guo Y, Shan Q, Gong Y, Lin J, Shi F, Shi R and Yang X: Curcumin induces apoptosis via simultaneously targeting AKT/mTOR and RAF/MEK/ERK survival signaling pathways in human leukemia THP-1 cells. Pharmazie. 69:229–233. 2014.PubMed/NCBI
24	Zhao G, Han X, Zheng S, Li Z, Sha Y, Ni J, Sun Z, Qiao S and Song Z: Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells. Oncol Rep. 35:1065–1074. 2016. View Article : Google Scholar : PubMed/NCBI
25	Link A, Balaguer F, Shen Y, Lozano JJ, Leung HC, Boland CR and Goel A: Curcumin modulates DNA methylation in colorectal cancer cells. PLoS One. 8:e577092013. View Article : Google Scholar : PubMed/NCBI
26	Wu P, Huang R, Xiong YL and Wu C: Protective effects of curcumin against liver fibrosis through modulating DNA methylation. Chin J Nat Med. 14:255–264. 2016.PubMed/NCBI
27	Agrawal DK and Mishra PK: Curcumin and its analogues: Potential anticancer agents. Med Res Rev. 30:818–860. 2010.PubMed/NCBI
28	Naksuriya O, Okonogi S, Schiffelers RM and Hennink WE: Curcumin nanoformulations: A review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment. Biomaterials. 35:3365–3383. 2014. View Article : Google Scholar : PubMed/NCBI
29	Marquardt JU, Gomez-Quiroz L, Camacho Arreguin LO, Pinna F, Lee YH, Kitade M, Dominguez MP, Castven D, Breuhahn K, Conner EA, et al: Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. J Hepatol. 63:661–669. 2015. View Article : Google Scholar : PubMed/NCBI
30	Hu A, Huang JJ, Jin XJ, Li JP, Tang YJ, Huang XF, Cui HJ, Xu WH and Sun GB: Curcumin suppresses invasiveness and vasculogenic mimicry of squamous cell carcinoma of the larynx through the inhibition of JAK-2/STAT-3 signaling pathway. Am J Cancer Res. 5:278–288. 2014.PubMed/NCBI
31	Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY, Saw CL, Cheung KL and Kong AN: Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. AAPS J. 13:606–614. 2011. View Article : Google Scholar : PubMed/NCBI