Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells.
Iodine-131 (131I) has been used both in unconjugated form and conjugated to antibody derivates (i.e., radioimmunotherapy; RIT) to treat malignant diseases. The mechanisms by which 131I-irradiation causes growth retardation are, however, inadequately understood. The aim of this study was to elucidate the sequential molecular and cellular events that initiate cell death in HeLa Hep2 cells exposed to 131I. In this paper, HeLa Hep2 cells were found to display a transient G2-M arrest following irradiation, but then reentered the cell cycle still containing unrepaired cellular damage. An increase of multipolar mitotic spindles, as well as a significant increase in centrosome numbers from 8.8% +/- 1.9% in controls to 54.7% +/- 2.2% in irradiated cells, was observed (p < 0.0001). A subsequent failure of cytokinesis caused the cells to progress into mitotic catastrophe. This was accompanied by the formation of giant cells with multiple nuclei, multilobulated nuclei, and an increased frequency of polyploidy cells. A fraction of the cells also displayed apoptotic features, including the activation of initiator caspases-2, -8, -9, and effector caspase-3, as well as cleavage of poly(ADP-ribose) polymerase, a cell-death substrate for active caspase-3. These findings demonstrate that mitotic catastrophes and the activation of a delayed type of apoptosis might be important mechanisms involved in cell death following the RIT of solid tumors with -emitting radionuclides, such as 131I.
Eriksson
David
D
Department of Immunology, Umeå University, Umeå, Sweden.
Blomberg
Jeanette
J
Lindgren
Theres
T
Löfroth
Per-Olov
PO
Johansson
Lennart
L
Riklund
Katrine
K
Stigbrand
Torgny
T
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000528:radiation effects; D004789:Enzyme Activation; D005434:Flow Cytometry / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000494:pharmacology*; D008856:Microscopy, Fluorescence / Q000379:methods; D008938:Mitosis; D009369:Neoplasms / Q000532:radiotherapy*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016499:Radioimmunotherapy / Q000379:methods
D007457:Iodine Radioisotopes; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases