9-O-acetyl GD3 protects tumor cells from apoptosis.
The ganglioside GD3 (Neu5Ac alpha8Neu5Ac alpha3Gal beta4GlcCer) is an intracellular lipid messenger that induces apoptosis by targeting mitochondria in various cell types. GD3 can also promote apoptosis when externally added to cells. Previous studies showed that the proapoptotic effects of GD3 can be counteracted by 9-O-acetylation. To determine whether 9-O-acetyl GD3 (acGD3) has a general antiapoptotic potential, the apoptosis-sensitive Jurkat cell line and an apoptosis-sensitive variant of the cell line Molt-4 were preincubated with micromolar concentrations of acGD3 and then treated with inducers of apoptosis. A reduced apoptotic index and an increased cell viability were observed. On the other hand, when the Jurkat cells were treated with GD3 for extended periods of time, a population was selected that was resistant to apoptosis induction by N-acetyl sphingosine as well as by the anti-leukemic drug daunorubicin. Comparative analysis of gangliosides revealed the formation of acGD3 in the resistant Jurkat cells that was not found in the apoptosis-sensitive cells. Conversely, exposing the acGD3 positive and apoptosis-resistant cell line Molt-4 to the O-deacetylating activity of salicylate resulted in a complete disappearance of acGD3 and an enhanced sensitivity to N-acetyl sphingosine-mediated apoptosis. Formation of acGD3 might thus represent a new mechanism how tumor cells can escape apoptosis.
Kniep
Bernhard
B
Institute of Immunology, Technical University of Dresden, Dresden, Germany. b_kniep@rcs.urz.tu-dresden.de
Kniep
Eva
E
Ozkucur
Nurdan
N
Barz
Steffen
S
Bachmann
Michael
M
Malisan
Florence
F
Testi
Roberto
R
Rieber
Ernst Peter
EP
D000107:Acetylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005732:Gangliosides / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D005732:Gangliosides; C064769:N-acetylsphingosine; C049132:9-O-acetyl-GD3 ganglioside; D013110:Sphingosine; D003630:Daunorubicin