17AEP-GA, an HSP90 antagonist, is a potent inhibitor of glioblastoma cell proliferation, survival, migration and invasion

Miekus,Katarzyna; Kijowski,Jacek; Sekuła,Małgorzata; Majka,Marcin

doi:10.3892/or.2012.1996

17AEP-GA, an HSP90 antagonist, is a potent inhibitor of glioblastoma cell proliferation, survival, migration and invasion

Authors:
- Katarzyna Miekus
- Jacek Kijowski
- Małgorzata Sekuła
- Marcin Majka
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Affiliations: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University School of Medicine, Cracow, Poland
Published online on: August 27, 2012 https://doi.org/10.3892/or.2012.1996
Pages: 1903-1903

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Abstract

Glioblastoma multiforme (GBM) is the most frequent and the most malignant human brain tumor. The expression of receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is strongly increased in GBM, where they promote tumor proliferation, cell survival, migration, invasion and angiogenesis. We used geldanamycins (GAs) (inhibitors of HSP90) in order to block glioblastoma growth and HGF-dependent cell migration and invasion. The effect of GAs on three GBM cell lines was tested and we found their antiproliferative effect on tumor cells. The maximum level of inhibition reached 70%. After treatment with GAs, cells also became apoptotic as determined by Annexin V-positive staining and activation of the caspase-3 pathway. We examined the expression and activity of the MET receptor on GBM cell lines and we observed phosphorylation of AKT and MAPK after HGF stimulation by western blot analysis. Since GBM cells express high level of MET receptor and were shown to respond to HGF by increased motility we tested if GAs could negatively affect GBM cell movement. In our study, we found that GAs inhibited the chemotaxis of glioblastoma cells toward the hepatocyte growth factor gradient. The GAs also blocked migration of tumor cells through a Matrigel layer in invasion assays. The strongest inhibitory effect was observed for GA and its analog, 17AEP-GA. Based on our results, GAs, particularly 17AEP-GA, could be considered as a new potential agent to treat glioblastoma multiforme.

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1	McLendon RE and Halperin EC: Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer. 98:1745–1748. 2003. View Article : Google Scholar : PubMed/NCBI
2	Navas-Acién A, Pollán M, Gustavsson P, Floderus B, Plato N and Dosemeci M: Interactive effect of chemical substances and occupational electromagnetic field exposure on the risk of gliomas and meningiomas in Swedish men. Cancer Epidemiol Biomarkers Prev. 11:1678–1683. 2002.
3	Galloway TJ, Indelicato DJ, Amdur RJ, Swanson EL, Smith AA and Marcus RB: Second tumors in pediatric patients treated with radiotherapy to the central nervous system. Am J Clin Oncol. 35:279–283. 2011. View Article : Google Scholar : PubMed/NCBI
4	Krishnan S, Wade R and Moorman AV: Temporal changes in the incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council trials, 1985–2001. Leukemia. 24:450–459. 2010.PubMed/NCBI
5	Cordier S, Monfort C, Filippini G, et al: Parental exposure to polycyclic aromatic hydrocarbons and the risk of childhood brain tumors: The SEARCH International Childhood Brain Tumor Study. Am J Epidemiol. 159:1109–1116. 2004. View Article : Google Scholar : PubMed/NCBI
6	Molina JR, Hayashi Y, Stephens C and Georgescu MM: Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia. 12:453–463. 2010.PubMed/NCBI
7	Sauvageot CM, Weatherbee JL, Kesari S, et al: Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol. 11:109–121. 2009. View Article : Google Scholar : PubMed/NCBI
8	Abounader R and Laterra J: Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol. 7:436–451. 2005. View Article : Google Scholar : PubMed/NCBI
9	Mazzone M and Comoglio PM: The Met pathway: master switch and drug target in cancer progression. FASEB J. 20:1611–1621. 2006. View Article : Google Scholar : PubMed/NCBI
10	Lesko E and Majka M: The biological role of HGF-MET axis in tumor growth and development of metastasis. Front Biosci. 13:1271–1280. 2008. View Article : Google Scholar : PubMed/NCBI
11	Jiang W, Hiscox S, Matsumoto K and Nakamura T: Hepatocyte growth factor/scatter factor, its molecular, cellular and clinical implications in cancer. Crit Rev Oncol Hematol. 29:209–248. 1999. View Article : Google Scholar : PubMed/NCBI
12	Weidner KM, Sachs M and Birchmeier W: The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol. 121:145–154. 1993. View Article : Google Scholar
13	Pratt WB and Toft DO: Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood). 228:111–133. 2003.PubMed/NCBI
14	Maulik G, Kijima T, Ma PC, et al: Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res. 8:620–627. 2002.PubMed/NCBI
15	Workman P: Altered states: selectively drugging the Hsp90 cancer chaperone. Trends Mol Med. 10:47–51. 2004. View Article : Google Scholar : PubMed/NCBI
16	Whitesell L, Mimnaugh EG, De Costa B, Myers CE and Neckers LM: Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA. 91:8324–8328. 1994. View Article : Google Scholar
17	Goetz MP, Toft DO, Ames MM and Erlichman C: The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol. 14:1169–1176. 2003. View Article : Google Scholar : PubMed/NCBI
18	Ochel HJ, Eichhorn K and Gademann G: Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones. Cell Stress Chaperones. 6:105–112. 2001. View Article : Google Scholar : PubMed/NCBI
19	Lesko E, Gozdzik J, Kijowski J, Jenner B, Wiecha O and Majka M: HSP90 antagonist, geldanamycin, inhibits proliferation, induces apoptosis and blocks migration of rhabdomysoracoma cells in vitro and seeding into bone marrow in vivo. Anticancer Drugs. 18:1173–1181. 2007. View Article : Google Scholar : PubMed/NCBI
20	Ramanathan RK, Trump DL, Eiseman JL, et al: Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res. 11:3385–3391. 2005. View Article : Google Scholar
21	Xie Q, Thompson R, Hardy K, et al: A highly invasive human glioblastoma pre-clinical model for testing therapeutics. J Transl Med. 6:772008. View Article : Google Scholar : PubMed/NCBI
22	Zagzag D, Nomura M, Friedlander DR, Blanco CY, Gagner JP, Nomura N and Newcomb EW: Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. J Cell Physiol. 196:394–402. 2003. View Article : Google Scholar : PubMed/NCBI
23	Lukasiewicz E, Miekus K, Kijowski J, et al: High anti tumor activity against rhabdomyosarcoma cells and low normal cells cytotoxicity of heat shock protein 90 inhibitors, with special emphasis on 17- (2-(pyrrolidin-1-yl)ethyl)-aminno-17-demethoxy-geldanamycin. J Physiol Pharmacol. 60:161–166. 2009.
24	Solit DB, Basso AD, Olshen AB, Scher HI and Rosen N: Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res. 63:2139–2144. 2003.PubMed/NCBI
25	van Engeland M, Nieland LJ, Ramaekers FC, Schutte B and Reutelingsperger CP: Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry. 31:1–9. 1998.PubMed/NCBI
26	Hardy KM, Yatskievych TA, Konieczka J, Bobbs AS and Antin PB: FGF signalling through RAS/MAPK and PI3K pathways regulates cell movement and gene expression in the chicken primitive streak without affecting E-cadherin expression. BMC Dev Biol. 11:202011. View Article : Google Scholar
27	Miekus K, Jarocha D, Trzyna E and Majka M: Role of I-TAC-binding receptors CXCR3 and CXCR7 in proliferation, activation of intracellular signaling pathways and migration of various tumor cell lines. Folia Histochem Cytobiol. 48:104–111. 2010. View Article : Google Scholar : PubMed/NCBI
28	Xie Q, Gao CF, Shinomiya N, et al: Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion. Oncogene. 24:3697–3707. 2005. View Article : Google Scholar : PubMed/NCBI
29	Supko JG, Hickman RL, Grever MR and Malspeis L: Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 36:305–315. 1995. View Article : Google Scholar : PubMed/NCBI