Abstract
The Growth Differentiation Factor-15 gene (GDF15) is a member of TGF-b superfamily and this cytokine family is considered to be a promising target for cancer therapy. The purpose of this study was to investigate the effect of tumor derived GDF15 on proliferation and radiosensitivity of breast cancer cells in vitro and in vivo. A mouse breast cancer LM2 cell line with stable transfection of full-length mouse GDF15 cDNA was established. Cell growth and proliferation was observed using WST assay and impedance-based method. Radiation induced GDF15 and TGF-b1 expression was determined by qRT-PCR. Radiosensitivity was measured by a colony formation assay in vitro and by a tumor growth delay assay in vivo. Cells with more than a 10-fold increase in GDF15 expression had a higher growth rate than parental control cells in vitro and in vivo. The radiation induced elevation of the expression of TGFb1 was reduced in GDF15 overexpressing cells. GDF15 may play a role in the radiation response of breast cancer cells by effecting cell survival, inhibiting radiation-induced cell death, and inhibiting the TGF-b1 related cytotoxic action.
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Staff A.C., Bock A.J., Becker C., Kempf T., Wollert K.C., Davidson B., Growth differentiation factor-15 as a prognostic biomarker in ovarian cancer, Gynecol. Oncol., 2010, 118, 237–243
Wallin U., Glimelius B., Jirström K., Darmanis S., Nong R.Y., Pontén F., et al., Growth differentiation factor 15: a prognostic marker for recurrence in colorectal cancer, Br. J. Cancer., 2011, 104, 1619–1627
Suesskind D., Schatz A., Schnichels S., Coupland S.E., Lake S.L., Wissinger B., et al., GDF-15: a novel serum marker for metastases in uveal melanoma patients, Graefes Arch. Clin. Exp. Ophthalmol., 2012, 250, 887–895
Albertoni M., Shaw P.H., Nozaki M., Godard S., Tenan M., Hamou M.F., et al., Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1, Oncogene, 2002, 21, 4212–4219
Wilson L.C., Baek S.J., Call A., Eling T.E., Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is induced by genistein through the expression of p53 in colorectal cancer cells, Int. J. Cancer., 2003, 105, 747–753
Jurisic V., Srdic-Rajic T., Konjevic G., Bogdanovic G., Colic M., TNF-α induced apoptosis is accompanied with rapid CD30 and slower CD45 shedding from K-562 cells, J. Membr. Biol., 2011, 239, 115–122
Chen S.J., Karan D., Johansson S.L., Lin F.F., Zeckser J., Singh A.P., et al., Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells, Prostate, 2007, 67, 557–571
Baek K.E., Yoon S.R., Kim J.T., Kim K.S., Kang S.H., Yang Y., et al., Upregulation and secretion of macrophage inhibitory cytokine-1 (MIC-1) in gastric cancers, Clin. Chim. Acta, 2009, 401, 128–133
Brown D.A., Ward R.L., Buckhaults P., Liu T., Romans K.E., Hawkins N.J., et al., MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma, Clin. Cancer Res., 2003, 9, 2642–2650
Selander K.S., Brown D.A., Sequeiros G.B., Hunter M., Desmond R., Parpala T., et al., Serum macrophage inhibitory cytokine-1 concentrations correlate with the presence of prostate cancer bone metastases, Cancer Epidemiol. Biomarkers Prev., 2007, 16, 532–537
Huh S.J., Chung C.Y., Sharma A., Robertson G.P., Macrophage Inhibitory Cytokine-1 Regulates Melanoma Vascular Development, Am. J. Pathol., 2010, 176, 2948–2957
Hegyesi H., Sándor N., Schilling-Tóth B., Kis E., Lumniczky K., Sáfrány G., Differentially expressed genes associated with low-dose gamma radiation: Growth Differentiation Factor (GDF-15) as a radiation response gene and radiosensitizing target, In: Gómez-Tejodor G.G., Fuss M.C. (Eds.), Radiation Damage in Biomolecular Systems — Biological and Medical Physics, Biomedical Engineering, Springer, 2012
Kruse J.J., Floot B.G., te Poele J.A., Russell N.S., Stewart F.A., Radiation-induced activation of TGFbeta signaling pathways in relation to vascular damage in mouse kidneys, Radiat. Res., 2009, 171, 188–197
Rodemann H.P., Binder A., Burger A., Güven N., Löffler H., Bamberg M., The underlying cellular mechanism of fibrosis, Kidney Int. Suppl. 1996, 54, S32–36
Barcellos-Hoff M.H., How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues, Radiat. Res., 1998, 150, S109–120
Boerma M., Roberto K.A., Hauer-Jensen M., Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol, Int. J. Radiat. Oncol. Biol. Phy., 2008, 72, 170–177
Krüse J.J., Bart C.I., Visser A., Wondergem J., Changes in transforming growth factor-beta (TGFbeta 1), procollagen types I and II mRNA in the rat heart after irradiation, Int. J. Radiat. Biol., 1999, 75, 1429–1436
Munshi A., Hobbs M., Meyn R.E., Clonogenic Cell Survival Assay, In: Blumenthal R.D. (Ed.), Chemosensitivity — Volume I: In Vitro Assays, Springer, 2005
Hegyesi H., Lambert J.R., Sándor N., Scilling-Tóth B., Sáfrány G., Validation of Growth Differentiation Factor (GDF-15) as a Radiation Response Gene and Radiosensitizing Target in Mammary Adenocarcinoma Model, In: Done S.J. (Ed.), Breast Cancer — Recent Advances in Biology, Imaging and Therapeutics, InTech. 2011
Ozsvári B., Puskás L.G., Nagy L.I., Kanizsai I., Gyuris M., Madácsi R., et al., A cell-microelectronic sensing technique for the screening of cytoprotective compounds, Int. J. Mol. Med., 2010, 25, 525–530
Kürti L., Veszelka S., Bocsik A, Dung N.T., Ozsvári B., Puskás L.G., Kittel A, Szabó-Révész P., Deli M.A., The effect of sucrose esters on a culture model of the nasal barrier, Toxicol. In Vitro, 2012, 26, 445–454
Kürti L., Veszelka S., Bocsik A., Ozsvári B., Puskás L.G., Kittel A., Szabó-Révész P., Deli M.A., Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability, Cytotechnology, 2013, 65, 395–406
Kiss L., Walter F.R., Bocsik A., Veszelka S., Ozsvári B., Puskás LG., Szabó-Révész P., Deli M.A., Kinetic analysis of the toxicity of pharmaceutical excipients Cremophor EL and RH40 on endothelial and epithelial cells, J. Pharm. Sci., 2013, 102, 1173–1181
Veszelka S., Tóth A.E., Walter F.R., Datki Z., Mózes E., Fülöp L., et al., Docosahexaenoic acid reduces amyloid-β induced toxicity in cells of the neurovascular unit, J. Alzheimers Dis., 2013, 36, 487–501
Liu T., Bauskin A.R., Zaunders J., Brown D.A., Pankhurst S., Russell P.J., et al., Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells, Cancer Res., 2003, 63, 5034–5040
Roth P., Junker M., Tritschler I., Mittelbronn M., Dombrowski Y., Breit S.N., GDF-15 contributes to proliferation and immune escape of malignant gliomas, Clin. Cancer Res., 2010, 16, 3851–3859
Baek S.J., Kim K.S., Nixon J.B., Wilson L.C., Eling T.E., Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities, Mol. Pharmacol., 2001, 59, 901–908
Graichen R., Liu D., Sun Y., Lee K.O., Lobie P.E., Autocrine human growth hormone inhibits placental transforming growth factor-beta gene transcription to prevent apoptosis and allow cell cycle progression of human mammary carcinoma cells, J. Biol. Chem., 2002, 277, 26662–26672
Boyle G.M., Pedley J., Martyn A.C., Banducci K.J., Strutton G.M., Brown D.A., et al., Macrophage inhibitory cytokine-1 is overexpressed in malignant melanoma and is associated with tumorigenicity, J. Invest. Dermatol., 2009, 129, 383–391
Xu J., Kimball T.R., Lorenz J.N., Brown D.A., Bauskin A.R., Klevitsky R., et al., GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation, Circ. Res., 2006, 98, 342–350
de Jager S.C., Bermúdez B., Bot I., Koenen R.R., Bot M., Kavelaars A., et al., Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis, J. Exp. Med., 2011, 208, 217–225
Kim K.K., Lee J.J., Yang Y., You K.H., Lee J.H., Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells, Carcinogenesis, 2008, 29, 704–712
Ferrari N., Pfeffer U., Dell’Eva R., Ambrosini C., Noonan D.M., Albini A., The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide, Clin. Cancer. Res., 2005, 11, 4610–4619
Martin M., Vozenin M.C., Gault N., Crechet F., Pfarr C.M., Lefaix J.L., Coactivation of AP-1 activity and TGF-beta1 gene expression in the stress response of normal skin cells to ionizing radiation, Oncogene, 1997, 15, 981–989
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Schilling-Tóth, B., Sándor, N., Walter, F.R. et al. Role of GDF15 in radiosensitivity of breast cancer cells. cent.eur.j.biol. 9, 982–992 (2014). https://doi.org/10.2478/s11535-014-0328-8
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DOI: https://doi.org/10.2478/s11535-014-0328-8