BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells.
Conditionally BCL-xL-overexpressing LNT-229 Tet-On glioma cell clones were generated to investigate whether the 'antiapoptosis phenotype' and the 'motility phenotype' mediated by BCL-2 family proteins in glioma cells could be separated. BCL-xL induction led to an immediate and concentration-dependent protection of LNT-229 cells from apoptosis. BCL-xL induction for up to 3 days did not result in altered invasiveness. In contrast, long-term BCL-xL induction for 21 days resulted in increased transforming growth factor-beta2 expression, and in metalloproteinase-2 and -14 dependent, but integrin independent, increased invasiveness. Withdrawal of doxycycline (Dox) abolished the protection from apoptosis whereas the 'invasion phenotype' remained stable. Dox stimulation of BCL-xL-inducible LNT-229 cells conferred infiltrative growth to BCL-xL-positive glioma cells in vivo and reduced the survival of tumor-bearing mice. These data allow to dissect a direct antiapoptotic action of BCL-xL from an indirect effect, presumably mediated by altered gene expression, which modifies tumor cell invasiveness in vitro and in vivo.
Weiler
M
M
Laboratory of Molecular Neuro-Oncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, Tübingen D-72076, Germany.
Bähr
O
O
Hohlweg
U
U
Naumann
U
U
Rieger
J
J
Huang
H
H
Tabatabai
G
G
Krell
H W
HW
Ohgaki
H
H
Weller
M
M
Wick
W
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D005910:Glioma / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D006801:Humans; D015151:Immunoblotting; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053781:Transforming Growth Factor beta2; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics / Q000502:physiology*
C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D051020:bcl-X Protein; D020778:Matrix Metalloproteinase 2; D004318:Doxycycline