Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-09, Vol.102 (36), p.12771-12776
• Main Authors: Gutterman, J.U, Lai, H.T, Yang, P, Haridas, V, Gaikwad, A, Marcus, S
• Format: Article
• Language: English
• Subjects: Acacia; Acacia victoriae; Anaphase-Promoting Complex-Cyclosome; antineoplastic agents; Antineoplastic Agents - pharmacology; avicin G; Biological Sciences; cell division; Cell growth; Cell Membrane Permeability - drug effects; Cell nucleus; Cell Proliferation - drug effects; Cellular biology; chemical reactions; Cultured cells; Cytokines; Cytokinesis; Cytokinesis - drug effects; Drug Resistance, Fungal; fungal proteins; guanosinetriphosphatase; Inhibitor drugs; Lawns; Mutation - genetics; Oxidative stress; Protein Binding; Proteins; rho GTP-Binding Proteins - deficiency; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; Saponins - pharmacology; Schizosaccharomyces - cytology; Schizosaccharomyces - drug effects; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins; T lymphocytes; Terpenes - pharmacology; triterpenoids; Tumors; ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligase Complexes - genetics; Ubiquitin-Protein Ligase Complexes - metabolism; Ubiquitins; Up-Regulation; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505758102

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 micromolar) exhibited a shrunken morphology, indicating that avicin G adversely affects cell integrity. Cells treated with a sublethal concentration of avicin G (6.5 micromolar) 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.