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

Abstract

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 M) exhibited a shrunken morphology, indicating that avicin G adversely affects cell integrity. Cells treated with a sublethal concentration of avicin G (6.5 M) 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 cAMP͞PKA 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 and͞or ubiquitination function have been demonstrated as in cancer, fibrosis, and inflammation.A major goal in clinical cancer research is to discover compounds that selectively inhibit the growth of cancer cells without adversely affecting normal cell growth. A series of studies with a recently discovered family of triterpenoid compounds, the avicins, have identified cancer and inflammatory diseases as potential clinical targets (1-6). Originally isolated from the Australian desert tree Acacia victoriae, avicins have been shown to selectively inhibit the growth of tumor cells from a wide variety of tissue origins (1-6). Moreover, avicin treatment resulted in a dramatic reduction in the frequencies of both H-ras mutations and aneuploidy in a mouse model for skin carcinogenesis (4), as well as decreased p53 mutations in a murine UVB skin model (3). The molecular mechanisms by which avicins inhibit tumor cell growth are not well defined. However, there is evidence that they affect multiple cellular processes, including activation of apoptosis and cellular stress response pathways, as well as growth factor signaling, inflammation, and oxidative stress response (1-6).Elucidation of the underlying mechanisms by which avicins inhibit cell growth will greatly facilitate the rational designing and testing of improved drug analogs and could potentially result in the identification of novel targets for cancer intervention as well as new molecu...

Triterpenoid saponins from Albizia lebbeck (L.) Benth and their inhibitory effect on the survival of high grade human brain tumor cells

“…Indeed, avicin D-mediated cell death has been reported to be associated with the activation of the death receptor-caspase-8 pathway. 35 Avicins appear also to affect phospholipid-dependent processes, 36 pathway. 35 Moreover, it has recently been shown that some avicins may increase the level of ubiquitinated proteins in human Jurkat T cells possibly through an up-regulation of ubiquitin ligase activity.…”

“…35 Moreover, it has recently been shown that some avicins may increase the level of ubiquitinated proteins in human Jurkat T cells possibly through an up-regulation of ubiquitin ligase activity. 36 However, avicins seem to have other, and yet only partially identified, molecular targets. 37 Lebbeckosides A-B, two new avicin analogs isolated from Albizia lebbeck, might therefore be highly useful to further decipher the mechanism of action of this triterpene saponin and obtain new structure-activity relationship data.…”

Impact of Quillaja saponaria saponins on grapevine ecosystem organisms

“…Avicin G used at 0.02 mg ml -1 has been shown to be sufficient to inhibit Schizosaccharomyces pombe growth and induce a strong cytokinesisdefective phenotype (multiseptated cells) as well as a shrunken cellular morphology (Gutterman et al 2005). In a wider study Miyakoshi et al (2000) have described how Yucca schidigera steroidal saponins were effective against a wide range of wild S. cerevisiae but also other dermatophytic, food-deteriorating and film-foaming yeast species that spoil soy sauce.…”

Chemistry and pharmacology of saponins: special focus on cytotoxic properties

“…The authors also reported mitochondrial perturbation, chemoprevention, and inhibition of nuclear factor κB, concluding that triterpenoid saponins from A. victoriae have potential as novel anticancer agents. [37][38][39][40][41][42] Furthermore, autophagy-induced cell death which could be regulated by treatment with chloroquine was also tested, and it was concluded that avicin D-induced autophagic cell death can be abrogated by knockdown of tuberous sclerosis complex 2, which is a key mediator linking AMP-activated protein kinase, and mammalian target of rapamycin (mTOR). This validated autophagic cell death in the presence of avicins.…”