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Weightlessness Induced Apoptosis in Normal Thyroid Cells and Papillary Thyroid Carcinoma Cells via Extrinsic and Intrinsic Pathways

Institute of Clinical Pharmacology and Toxicology (P.K., H.P., M.P., D.G.), Benjamin Franklin Medical Center, Institute of Anatomy (M.S., G.S.-T.), and Klinik für Unfall und Wiederherstellungschirurgie (M.I.), Benjamin Franklin Medical Center, Freie Universität Berlin, 14195 Berlin, Germany; Space Biology Group (A.C.), ETH Zurich, 8005 Zurich, Switzerland; Dipartmento di Patologia e Medicina Sperimentale e Clinica, University of Udine Medical School (F.C.), 33100 Udine, Italy; Clinic of Nuclear Medicine, University of Regensburg (J.S., C.E.), 93042 Regensburg, Germany; and Max Planck Institute of Biochemistry (J.B.), 82152 Martinsried, Germany

Address all correspondence and requests for reprints to: Daniela Grimm, M.D., Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, Garystrasse 5, D-14195 Berlin, Germany. E-mail: dgrimm{at}zedat.fu-berlin.de.

Apoptosis plays a pivotal role in development, tissue homeostasis, cancer, immune defense, and response to weightlessness. It can be initiated by external signals via death receptors, but may also emerge from mitochondria. We exposed mitochondria-rich thyroid carcinoma cells (ONCO-DG1 cell line) and normal thyroid cells (HTU-5) to conditions of simulated microgravity. After 24 h, 10% of the cancer cells had entered a Fas-dependent apoptotic pathway, but destruction and redistribution of mitochondria, microtubuli disruption, and caspase-3 activation were also detected, demonstrating the activation of extrinsic as well as intrinsic pathways. Furthermore, ONCO-DG1 cells grown on the clinostat showed elevated amounts of Bax, but reduced quantities of bcl-2. In addition, signs of apoptosis became detectable, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling, 4',6-diamidino-2-phenylindole staining, and 85-kDa apoptosis-related cleavage fragments. These fragments resulted from enhanced 116-kDa poly(ADP-ribose)polymerase activity and apoptosis. Apoptosis was also detected in normal HTU-5 cells, as demonstrated by electron microscopy, activation of caspase-3, increases in Fas and Bax, and elevation of 85-kDa apoptosis-related cleavage fragments resulting from enhanced poly(ADP-ribose) polymerase activity. Gravitational unloading affects the mitochondria and thereby may trigger apoptosis in thyroid cells subjected to weightlessness by clinorotation.

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