Weightlessness induced apoptosis in normal thyroid cells and papillary thyroid carcinoma cells via extrinsic and intrinsic pathways.
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.
Kossmehl
Peter
P
Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, 14195 Berlin, Germany.
Shakibaei
Mehdi
M
Cogoli
Augusto
A
Infanger
Manfred
M
Curcio
Francesco
F
Schönberger
Johann
J
Eilles
Christoph
C
Bauer
Johann
J
Pickenhahn
Holger
H
Schulze-Tanzil
Gundula
G
Paul
Martin
M
Grimm
Daniela
D
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002291:Carcinoma, Papillary; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D053495:Osteopontin; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012399:Rotation; D012795:Sialoglycoproteins / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology*; D013964:Thyroid Neoplasms; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism; D014893:Weightlessness; D019014:fas Receptor / Q000378:metabolism
D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D007797:Laminin; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D019014:fas Receptor; D053495:Osteopontin; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases