Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast.
Avicins comprise a class of triterpenoid compounds that exhibit tumor inhibitory activity. Here we show that avicin G is inhibitory to growth of the fission yeast Schizosaccharomyces pombe. S. pombe cells treated with a lethal concentration of avicin G (20 microM) exhibited a shrunken morphology, indicating that avicin G adversely affects cell integrity. Cells treated with a sublethal concentration of avicin G (6.5 microM) exhibited a strong cytokinesis-defective phenotype (multiseptated cells), as well as cell morphology defects. These phenotypes bear resemblance to those resulting from loss of Rho1 GTPase function in S. pombe. Indeed, Rho1-deficient S. pombe cells were strongly hypersensitive to avicin G, suggesting that the compound may perturb Rho1-dependent processes. Consistent with previously observed effects in human Jurkat T cells, avicin G treatment resulted in hyperaccumulation of ubiquitinated proteins in S. pombe cells. Interestingly, proteasome-defective S. pombe mutants were not markedly hypersensitive to avicin G, whereas an anaphase-promoting complex (mitotic ubiquitin ligase) mutant exhibited avicin G resistance, suggesting that the increase in levels of ubiquitinated proteins resulting from avicin G treatment may be due to increased protein ubiquitination, rather than inhibition of 26S proteasome activity. Mutants defective in the cAMP/PKA pathway also exhibited resistance to avicin G. Our results suggest that S. pombe will be a useful model organism for elucidating molecular targets of avicin G and serve as a guide to clinical application where dysfunctional aspects of Rho and/or ubiquitination function have been demonstrated as in cancer, fibrosis, and inflammation.
Gutterman
Jordan U
JU
Department of Molecular Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Lai
Hong T
HT
Yang
Peirong
P
Haridas
Valsala
V
Gaikwad
Amos
A
Marcus
Stevan
S
D064173:Anaphase-Promoting Complex-Cyclosome; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048749:Cytokinesis / Q000187:drug effects*; D025141:Drug Resistance, Fungal; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012503:Saponins / Q000494:pharmacology*; D012568:Schizosaccharomyces / Q000166:cytology* / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D012503:Saponins; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes; D025801:Ubiquitin; C478446:avicin G; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D020741:rho GTP-Binding Proteins; C511156:rho1 protein, S pombe