HIF-1α inhibition sensitizes pituitary adenoma cells to temozolomide by regulating MGMT expression

Chen,Wenna; Xiao,Zheng; Zhao,Yachao; Huang,Lina; Du,Ganqin

doi:10.3892/or.2013.2689

HIF-1α inhibition sensitizes pituitary adenoma cells to temozolomide by regulating MGMT expression

Authors:
- Wenna Chen
- Zheng Xiao
- Yachao Zhao
- Lina Huang
- Ganqin Du
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Affiliations: Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Neurosurgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
Published online on: August 22, 2013 https://doi.org/10.3892/or.2013.2689
Pages: 2495-2501

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Abstract

Suppression of hypoxia-inducible factor 1α (HIF-1α) has been shown to sensitize glioblastoma cells to temozolomide (TMZ) treatment via down-modulation of O6-methylguanine-DNA methyltransferase (MGMT) expression. To date, whether the efficacy of TMZ therapy is correlated with MGMT expression and whether HIF-1α suppression exerts similar effects in human pituitary adenoma cells have not been defined. In the present study, using an HIF-1α knockdown strategy and the HIF-1α inhibitor 2-methoxyestradiol (2ME), we demonstrated for the first time that HIF-1α suppression increases the efficacy of TMZ in human pituitary adenoma cells in vitro and in vivo. Our mechanistic study showed that HIF-1α suppression resulted in down-modulation of MGMT expression and decreased DNA damage repair ability as demonstrated by decreased RAD51 protein expression. These results suggest an HIF-1α-dependent regulation of MGMT expression in human pituitary adenoma cells, and HIF-1α knockdown or the HIF-1α inhibitor 2ME can confer TMZ sensitization in human pituitary adenomas. The clinical application of 2ME as an adjuvant therapy may be a potential approach to improve the efficacy of TMZ therapy for pituitary adenomas.

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1	Selman WR, Laws ER Jr, Scheithauer BW and Carpenter SM: The occurrence of dural invasion in pituitary adenomas. J Neurosurg. 64:402–407. 1986. View Article : Google Scholar : PubMed/NCBI
2	Scheithauer BW, Kovacs KT, Laws ER Jr and Randall RV: Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg. 65:733–744. 1986. View Article : Google Scholar : PubMed/NCBI
3	Kreutzer J and Fahlbusch R: Diagnosis and treatment of pituitary tumors. Curr Opin Neurol. 17:693–703. 2004. View Article : Google Scholar
4	Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B and Skogseid B: Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 13:2986–2991. 2007. View Article : Google Scholar : PubMed/NCBI
5	McCormack AI, McDonald KL, Gill AJ, Clark SJ, Burt MG, Campbell KA, Braund WJ, Little NS, Cook RJ, Grossman AB, Robinson BG and Clifton-Bligh RJ: Low O⁶-methylguanine- DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol. 71:226–233. 2009.
6	Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE, Horvath E and Kovacs K: Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm. Clin Endocrinol. 65:552–553. 2006. View Article : Google Scholar : PubMed/NCBI
7	Everhard S, Kaloshi G, Criniere E, Benouaich-Amiel A, Lejeune J, Marie Y, Sanson M, Kujas M, Mokhtari K, Hoang-Xuan K, Delattre JY and Thillet J: MGMT methylation: a marker of response to temozolomide in low-grade gliomas. Ann Neurol. 60:740–743. 2006. View Article : Google Scholar : PubMed/NCBI
8	Stupp R, Hegi ME, Gilbert MR and Chakravarti A: Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol. 25:4127–4136. 2007. View Article : Google Scholar : PubMed/NCBI
9	van Nifterik KA, van den Berg J, van der Meide WF, Ameziane N, Wedekind LE, Steenbergen RD, Leenstra S, Lafleur MV, Slotman BJ, Stalpers LJ and Sminia P: Absence of the MGMT protein as well as methylation of the MGMT promoter predict the sensitivity for temozolomide. Br J Cancer. 103:29–35. 2010.PubMed/NCBI
10	Persano L, Pistollato F, Rampazzo E, Della PA, Abbadi S, Frasson C, Volpin F, Indraccolo S, Scienza R and Basso G: BMP2 sensitizes glioblastoma stem-like cells to temozolomide by affecting HIF-1alpha stability and MGMT expression. Cell Death Dis. 3:e4122012. View Article : Google Scholar : PubMed/NCBI
11	Xiao Z, Liu Q, Zhao B, Wu J and Lei T: Hypoxia induces hemorrhagic transformation in pituitary adenomas via the HIF-1α signaling pathway. Oncol Rep. 26:1457–1464. 2011.PubMed/NCBI
12	Losa M, Mazza E, Terreni MR, McCormack A, Gill AJ, Motta M, Cangi MG, Talarico A, Mortini P and Reni M: Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases. Eur J Endocrinol. 163:843–851. 2010. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Ma Z, Xiao Z, Liu H, Dou Z, Feng X and Shi H: Chk1 knockdown confers radiosensitization in prostate cancer stem cells. Oncol Rep. 28:2247–2254. 2012.PubMed/NCBI
14	Yang J, Xiao Z, Li T, Gu X and Fan B: Erythropoietin promotes the growth of pituitary adenomas by enhancing angiogenesis. Int J Oncol. 40:1230–1237. 2012.PubMed/NCBI
15	Naumann SC, Roos WP, Jost E, Belohlavek C, Lennerz V, Schmidt CW, Christmann M and Kaina B: Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53. Br J Cancer. 100:322–333. 2009. View Article : Google Scholar : PubMed/NCBI
16	Sadones J, Michotte A, Veld P, Chaskis C, Sciot R, Menten J, Joossens EJ, Strauven T, D’Hondt LA, Sartenaer D, et al: MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma. Eur J Cancer. 45:146–153. 2009. View Article : Google Scholar : PubMed/NCBI
17	van Nifterik KA, van den Berg J, Stalpers LJ, Lafleur MV, Leenstra S, Slotman BJ, Hulsebos TJ and Sminia P: Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines. Int J Radiat Oncol Biol Phys. 69:1246–1253. 2007.PubMed/NCBI
18	Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB and Herman JG: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 343:1350–1354. 2000. View Article : Google Scholar
19	Neff LM, Weil M, Cole A, Hedges TR, Shucart W, Lawrence D, Zhu JJ, Tischler AS and Lechan RM: Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists. Pituitary. 10:81–86. 2007. View Article : Google Scholar : PubMed/NCBI
20	Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O, Chanson P, Cortet-Rudelli C, Assaker R, et al: Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience. J Clin Endocrinol Metab. 95:4592–4599. 2010. View Article : Google Scholar : PubMed/NCBI
21	Sharma S, Salehi F, Scheithauer BW, Rotondo F, Syro LV and Kovacs K: Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer Res. 29:3759–3768. 2009.PubMed/NCBI
22	Baumann P and West SC: Role of the human RAD51 protein in homologous recombination and double-stranded-break repair. Trends Biochem Sci. 23:247–251. 1998. View Article : Google Scholar : PubMed/NCBI
23	Syro LV, Ortiz LD, Scheithauer BW, Lloyd R, Lau Q, Gonzalez R, Uribe H, Cusimano M, Kovacs K and Horvath E: Treatment of pituitary neoplasms with temozolomide: a review. Cancer. 117:454–462. 2011. View Article : Google Scholar : PubMed/NCBI
24	Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, et al: MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 26:2192–2197. 2008. View Article : Google Scholar
25	Takeshita A, Inoshita N, Taguchi M, Okuda C, Fukuhara N, Oyama K, Ohashi K, Sano T, Takeuchi Y and Yamada S: High incidence of low O⁶-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing’s disease. Eur J Endocrinol. 161:553–559. 2009.
26	Jackson SP and Bartek J: The DNA-damage response in human biology and disease. Nature. 461:1071–1078. 2009. View Article : Google Scholar : PubMed/NCBI
27	Levy A, Hall L, Yeudall WA and Lightman SL: p53 gene mutations in pituitary adenomas: rare events. Clin Endocrinol. 41:809–814. 1994. View Article : Google Scholar : PubMed/NCBI
28	Hagen T, D’Amico G, Quintero M, Palacios-Callender M, Hollis V, Lam F and Moncada S: Inhibition of mitochondrial respiration by the anticancer agent 2-methoxyestradiol. Biochem Biophys Res Commun. 322:923–929. 2004. View Article : Google Scholar : PubMed/NCBI
29	Pribluda VS, Gubish ER Jr, Lavallee TM, Treston A, Swartz GM and Green SJ: 2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate. Cancer Metastasis Rev. 19:173–179. 2000. View Article : Google Scholar : PubMed/NCBI
30	Verger E, Gil M, Yaya R, Vinolas N, Villa S, Pujol T, Quinto L and Graus F: Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys. 61:185–191. 2005. View Article : Google Scholar : PubMed/NCBI