TIMP-1-GPI in combination with hyperthermic treatment of melanoma increases sensitivity to FAS-mediated apoptosis |
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Authors: | Roghieh Djafarzadeh Valeria Milani Nicole Rieth Irene von Luettichau Petra S Skrablin Monika Hofstetter Elfriede Noessner Peter J Nelson |
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Institution: | 1.Medizinische Poliklinik,Ludwig-Maximilians-Universit?t München,Munich,Germany;2.Medical Clinic III,Ludwig-Maximilians-University of Munich,Munich,Germany;3.Department of Paediatrics,Technical University,Munich,Germany;4.Helmholz Zentrum Munich-Institute of Molecular Immunology,Munich,Germany |
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Abstract: | Resistance to apoptosis is a prominent feature of malignant melanoma. Hyperthermic therapy can be an effective adjuvant treatment
for some tumors including melanoma. We developed a fusion protein based on the tissue inhibitor of matrix metalloproteinase-1
linked to a glycosylphosphatidylinositol anchor (TIMP-1-GPI). The TIMP-1-GPI-fusion protein shows unique properties. Exogenous
administration of TIMP-1-GPI can result in transient morphological changes to treated cells including modulation of proliferation
and decreased resistance to apoptosis. The effect of TIMP-1-GPI on the biology of melanoma in the context of a defined hyperthermic
dose was evaluated in vitro. Clonogenic assays were used to measure cell survival. Gelatinase zymography determined secretion
of MMP-2 and MMP-9. Monoclonal antibody against FAS/CD95 was applied to induce apoptosis. The expression of pro- and anti-apoptotic
proteins and the secretion of immunoregulatory cytokines were then evaluated using Western blot and ELISA. TIMP-1-GPI combined
with a sub-lethal hyperthermic treatment (41.8°C for 2 h) suppressed tumor cell growth capacity as measured by clonogenic
assay. The co-treatment also significantly suppressed tumor cell proliferation, enhanced FAS receptor surface expression increased
tumor cell susceptibility to FAS-mediated killing. The increased sensitivity to FAS-induced apoptosis was linked to alterations
in the apoptotic mediators Bcl-2, Bax, Bcl-XL and Apaf-1. The agent works in concert with sub-lethal hyperthermic treatment
to render melanoma cells sensitive to FAS killing. The targeted delivery of TIMP-1-GPI to tumor environments in the context
of regional hyperthermic therapy could be optimized through the use of thermosensitive liposomes.
Elfriede Noessner, Peter J. Nelson are equal contributors. |
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Keywords: | TIMP-1-GPI Hyperthermic therapy Melanoma Apoptosis |
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