Thalidomide induces limb anomalies by PTEN stabilization, Akt suppression, and stimulation of caspase-dependent cell death.
Thalidomide, a drug used for the treatment of multiple myeloma and inflammatory diseases, is also a teratogen that causes birth defects, such as limb truncations and microphthalmia, in humans. Thalidomide-induced limb truncations result from increased cell death during embryonic limb development and consequential disturbance of limb outgrowth. Here we demonstrate in primary human embryonic cells and in the chicken embryo that thalidomide-induced signaling through bone morphogenetic proteins (Bmps) protects active PTEN from proteasomal degradation, resulting in suppression of Akt signaling. As a consequence, caspase-dependent cell death is stimulated by the intrinsic and Fas death receptor apoptotic pathway. Most importantly, thalidomide-induced limb deformities and microphthalmia in chicken embryos could be rescued by a pharmacological PTEN inhibitor as well as by insulin, a stimulant of Akt signaling. We therefore conclude that perturbation of PTEN/Akt signaling and stimulation of caspase activity is central to the teratogenic effects of thalidomide.
Knobloch
Jürgen
J
University of Cologne, Medical Clinic III, Department of Pneumology, Kerpener Strasse 62, D-50924 Cologne, Germany. juergen.knobloch@uk-koeln.de
Schmitz
Ingo
I
Götz
Katrin
K
Schulze-Osthoff
Klaus
K
Rüther
Ulrich
U
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D018878:Limb Buds / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D017880:Limb Deformities, Congenital / Q000139:chemically induced / Q000196:embryology / Q000201:enzymology* / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D019014:fas Receptor; D013792:Thalidomide; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D020169:Caspases; D046988:Proteasome Endopeptidase Complex