Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia

Wang,Jian‑Yong; Jia,Xiu‑Hong; Xing,Hai‑Yan; Li,You‑Jie; Fan,Wen‑Wen; Li,Na; Xie,Shu‑Yang

doi:10.3892/mmr.2015.3469

Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia

Authors:
- Jian‑Yong Wang
- Xiu‑Hong Jia
- Hai‑Yan Xing
- You‑Jie Li
- Wen‑Wen Fan
- Na Li
- Shu‑Yang Xie
View Affiliations

Affiliations: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China, Department of Respiration, Binzhou People's Hospital, Binzhou, Shandong 256603, P.R. China, Department of Biochemistry and Molecular Biology, Key Laboratory of Tumour Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China, Department of Pediatrics, Women and Children Hospital of Qingdao, Qingdao, Shandong 266011, P.R. China
Published online on: March 11, 2015 https://doi.org/10.3892/mmr.2015.3469
Pages: 1457-1464

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

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood malignancy, deriving from T-cell progenitors in the thymus, and comprises 10‑15% of pediatric and 25% of adult primary ALL cases. Despite advances, 20% of pediatric and the majority of adult patients with T-ALL succumb to mortality from resistant or relapsed disease, and the survival rate for patients with resistant or relapsed T-ALL remains poor. Alterations in the expression of Forkhead box protein M1 (FoxM1) have been detected in several types of cancer, and the inhibition of FoxM1 has been investigated as therapeutic strategy in cancer. The present study investigated the effects of the inhibition of FoxM1 by thiostrepton in human T-ALL Jurkat cells. The cells were treated with different concentrations of thiostrepton, either alone or in combination with doxorubicin. Cell viability was measured using CCK-8 assays and the cell cycle distribution, apoptosis and cell-associated mean fluorescence intensity of intracellular doxorubicin were assessed using flow cytometric analysis. The mRNA and protein expression levels were detected by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. The inhibition of FoxM1 by thiostrepton significantly decreased the proliferation of the Jurkat cells proliferation in a time- and dose-dependent manner. Cell arrest at the G2/M phase, and apoptosis was significantly increased in the thiostrepton-treated Jurkat cells. Thiostrepton reduced the half maximal inhibitory concentration of doxorubicin in the Jurkat cells, and significantly enhanced the cytotoxicity of doxorubicin within the Jurkat cells by enhancing doxorubicin-induced apoptosis and increasing the accumulation of intracellular doxorubicin. Furthermore, the inhibition of FoxM1 by thiostrepton enhanced doxorubicin-induced apoptosis, possibly through a caspase-3-dependent pathway, and increased the accumuation of intracellular doxorubicin, possibly through downregulating the expression of glutathione S-transferase pi. Collectively, the results of the present study suggested that targeting FoxM1 with thiostrepton resulted in potent antileukemia activity and chemosensitizing effects in human T-ALL Jurkat cells.

View Figures

View References

1	Inaba H, Greaves M and Mullighan CG: Acute lymphoblastic leukaemia. Lancet. 381:1943–1955. 2013. View Article : Google Scholar : PubMed/NCBI
2	Bhojwani D and Pui CH: Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 14:e205–217. 2013. View Article : Google Scholar : PubMed/NCBI
3	Van Vlierberghe P and Ferrando A: The molecular basis of T cell acute lymphoblastic leukemia. J Clin Invest. 122:3398–3406. 2012. View Article : Google Scholar : PubMed/NCBI
4	Martelli AM, Lonetti A, Buontempo F, et al: Targeting signaling pathways in T-cell acute lymphoblastic leukemia initiating cells. Adv Biol Regul. 56:6–21. Apr 30–2014.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
5	Wierstra I and Alves J: FOXM1, a typical proliferation-associated transcription factor. Biol Chem. 388:1257–1274. 2007. View Article : Google Scholar : PubMed/NCBI
6	Koo CY, Muir KW and Lam EW: FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta. 1819:28–37. 2012. View Article : Google Scholar
7	Priller M, Pöschl J, Abrão L, et al: Expression of FoxM1 is required for the proliferation of medulloblastoma cells and indicates worse survival of patients. Clin Cancer Res. 17:6791–6801. 2011. View Article : Google Scholar : PubMed/NCBI
8	Xue YJ, Xiao RH, Long DZ, et al: Overexpression of FoxM1 is associated with tumor progression in patients with clear cell renal cell carcinoma. J Transl Med. 10:2002012. View Article : Google Scholar : PubMed/NCBI
9	Xia JT, Wang H, Liang LJ, et al: Overexpression of FOXM1 is associated with poor prognosis and clinicopathologic stage of pancreatic ductal adenocarcinoma. Pancreas. 41:629–635. 2012. View Article : Google Scholar : PubMed/NCBI
10	Xu N, Jia D, Chen W, et al: FoxM1 is associated with poor prognosis of non-small cell lung cancer patients through promoting tumor metastasis. PLoS One. 8:e594122013. View Article : Google Scholar : PubMed/NCBI
11	Li X, Qiu W, Liu B, et al: Forkhead box transcription factor 1 expression in gastric cancer: FOXM1 is a poor prognostic factor and mediates resistance to docetaxel. J Transl Med. 11:2042013. View Article : Google Scholar : PubMed/NCBI
12	Liu LL, Zhang DH, Mao X, Zhang XH and Zhang B: Over-expression of FoxM1 is associated with adverse prognosis and FLT3-ITD in acute myeloid leukemia. Biochem Biophys Res Commun. 446:280–285. 2014. View Article : Google Scholar : PubMed/NCBI
13	Myatt SS and Lam EW: The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 7:847–859. 2007. View Article : Google Scholar : PubMed/NCBI
14	Halasi M and Gartel AL: Suppression of FOXM1 sensitizes human cancer cells to cell death induced by DNA-damage. PLoS One. 7:e317612012. View Article : Google Scholar : PubMed/NCBI
15	Nakamura S, Hirano I, Okinaka K, et al: The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis. 31:2012–2021. 2010. View Article : Google Scholar : PubMed/NCBI
16	Zhang X, Zeng J, Zhou M, et al: The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia. Mol Cancer. 11:562012. View Article : Google Scholar : PubMed/NCBI
17	Mencalha AL, Binato R, Ferreira GM, Du Rocher B and Abdelhay E: Forkhead box M1 (FoxM1) gene is a new STAT3 transcriptional factor target and is essential for proliferation, survival and DNA repair of K562 cell line. PloS one. 7:e481602012. View Article : Google Scholar : PubMed/NCBI
18	Bhat UG, Halasi M and Gartel AL: FoxM1 is a general target for proteasome inhibitors. PLoS One. 4:e65932009. View Article : Google Scholar : PubMed/NCBI
19	Hegde NS, Sanders DA, Rodriguez R and Balasubramanian S: The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nat Chem. 3:725–731. 2011. View Article : Google Scholar : PubMed/NCBI
20	Hedge NS, Sanders DA, Rodriguez R and Balasubramanian S: The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nat Chem. 3:725–731. 2011. View Article : Google Scholar
21	Gartel AL: Thiostrepton, proteasome inhibitors and FOXM1. Cell Cycle. 10:4341–4342. 2011. View Article : Google Scholar : PubMed/NCBI
22	Halasi M, Schraufnagel DP and Gartel AL: Wild-type p53 protects normal cells against apoptosis induced by thiostrepton. Cell Cycle. 8:2850–2851. 2009. View Article : Google Scholar : PubMed/NCBI
23	Ahmed M, Uddin S, Hussain AR, et al: FoxM1 and its association with matrix metalloproteinases (MMP) signaling pathway in papillary thyroid carcinoma. J Clin Endocrinol Metab. 97:E1–13. 2012. View Article : Google Scholar
24	Wang M and Gartel AL: Micelle-encapsulated thiostrepton as an effective nanomedicine for inhibiting tumor growth and for suppressing FOXM1 in human xenografts. Mol Cancer Ther. 10:2287–2297. 2011. View Article : Google Scholar : PubMed/NCBI
25	Liu X, Li X, Wang L, et al: Realgar induces apoptosis in the chronic lymphocytic leukemia cell line MEC1. Mol Med Rep. 8:1866–1870. 2013.PubMed/NCBI
26	Ji BS, He L and Liu GQ: Reversal of p-glycoprotein-mediated multidrug resistance by CJX1, an amlodipine derivative, in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. Life Sci. 77:2221–2232. 2005. View Article : Google Scholar : PubMed/NCBI
27	Van Vlierberghe P, A mbesi-I mpiombato A, De Keersmaecker K, et al: Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia. Blood. 122:74–82. 2013. View Article : Google Scholar : PubMed/NCBI
28	Bhat UG, Halasi M and Gartel AL: Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS One. 4:e55922009. View Article : Google Scholar : PubMed/NCBI
29	Lin J, Zheng Y, Chen K, Huang Z, Wu X and Zhang N: Inhibition of FOXM1 by thiostrepton sensitizes medulloblastoma to the effects of chemotherapy. Oncol Rep. 30:1739–1744. 2013.PubMed/NCBI
30	Halasi M and Gartel AL: FOX(M1) news - it is cancer. Mol Cancer Ther. 12:245–254. 2013. View Article : Google Scholar : PubMed/NCBI
31	Zaffaroni N, Pennati M and Daidone MG: Survivin as a target for new anticancer interventions. J Cell Mol Med. 9:360–372. 2005. View Article : Google Scholar : PubMed/NCBI
32	Zhou L, Jing Y, Styblo M, Chen Z and Waxman S: Glutathione-S-transferase pi inhibits As2O3-induced apoptosis in lymphoma cells: involvement of hydrogen peroxide catabolism. Blood. 105:1198–1203. 2005. View Article : Google Scholar
33	Lourenco GJ, Lorand-Metze I, Delamain MT, et al: Polymorphisms of glutathione S-transferase mu 1, theta 1 and pi 1 genes and prognosis in Hodgkin lymphoma. Leuk Lymphoma. 51:2215–2221. 2010. View Article : Google Scholar
34	Ballerini S, Bellincampi L, Bernardini S, Iori R, Cortese C and Federici G: Analysis of GSTP1–1 polymorphism using real-time polymerase chain reaction. Clin Chim Acta. 329:127–132. 2003. View Article : Google Scholar : PubMed/NCBI
35	Song YN, Guo XL, Zheng BB, et al: Ligustrazine derivate DLJ14 reduces multidrug resistance of K562/A02 cells by modulating GSTπ activity. Toxicol In Vitro. 25:937–943. 2011. View Article : Google Scholar : PubMed/NCBI