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Demethyl fructiculin A (SCO-1) induces apoptosis by inducing reactive oxygen species in mitochondria

ABSTRACT: Demethyl fructiculin A is a diterpenoid quinone component of the exudates from Salvia corrugata (SCO-1) leafes. SCO-1 was recently reported to induce anoikis in mammalian cell lines via a molecular mechanism involving the presence of the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36, showed that SCO-1 was able to induce apoptosis also via alternate pathways. To contribute to a better characterization of the molecular mechanisms underlining the cytotoxic activity of SCO-1, we decided to pursue an unbiased pharmacogenomic approach by generating the gene expression profile of GBM TICs subjected to the administration of SCO-1 and comparing it with that of control cells exposed to the solvent. With this strategy we hypothesized to highlight those pathways and biological processes unlashed by SCO-1. Using this approach we unveiled that the main mechanism responsible for the SCO-1 pro-apoptotic effect is superoxide generation in mitochondria and that this molecule has potential chemotherapeutic properties that should be further investigated in GBM xenotransplant models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19846 | GEO | 2010/10/15

SECONDARY ACCESSION(S): PRJNA122071

REPOSITORIES: GEO

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Project description:Intracellular small-molecule signaling has drawn increasing attention due to its importance in bacterial physiology and host-pathogen interactions. Here, we show that a new quinone-sensing transcriptional regulator, QsbR (quinone-stress sensing and bleomycin resistance regulator), is important for bacterial stress response and virulence in S. aureus. The mutant strain of qsbR exhibits dramatically reduced staphylococcal virulence in a murine abscess model of infection. Moreover, the qsbR mutant shows an accumulation of riboflavin and an increased resistance to quinone stress and bleomycin compared to the wild-type strain Newman. Microarray analysis confirmed that QsbR impacts the expression of genes that are involved in quinone stress response, bleomycin resistance, riboflavin biosynthesis, and pathogenesis. DNase-I footprinting and gel shift assays suggest that QsbR not only directly regulates transcription of genes involved in quinone detoxification and bleomycin resistance, but is also subject to autoregulation by binding to the palindromic consensus sequence GTATAN(5)TATAC in their promoter regions. This binding could be disrupted by quinone treatment in vitro. Mass spectrometric analysis showed that wild-type QsbR, but not QsbRC5S with Cys5 mutated to Ser, could be alkylated at Cys5 by quinone. Further mutagenesis studies revealed that Cys5 plays a key role in quinone sensing as substitution of Cys5 with Ser renders the bacterium more sensitive to quinone stress. Our results demonstrate that QsbR is a quinone-sensing regulator that dramatically impacts staphylococcal virulence and stress response. Sample preparation for transcriptional analysis. For each strain, 2 clones were inoculated in TSB and collected from mid-log or stationary phase. Appropriate volumes from each of the 2 cultures per strain were pooled and added to 2 volumes of RNAprotect reagent (Qiagen). Cultures were centrifuged and cell pellets were stored at 4 ÂºC until RNA extraction. During the experiment, OD600 and viable cfu per ml were monitored for each of the cultures. This procedure was repeated 2 independent times to generate 2 samples at each time point for each strain.

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Demethyl fructiculin A (SCO-1) induces apoptosis by inducing reactive oxygen species in mitochondria

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