Jiang J, Jedinak A, Sliva DGanodermanontriol (GDNT) exerts its effect on growth and invasiveness of breast cancer cells through the down-regulation of CDC20 and uPA. Biochem Biophys Res Commun 415: 325-329

Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, IN, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 11/2011; 415(2):325-9. DOI: 10.1016/j.bbrc.2011.10.055
Source: PubMed


Ganoderma lucidum is a medicinal mushroom that has been recognized by Traditional Chinese Medicine (TCM). Although some of the direct anticancer activities are attributed to the presence of triterpenes-ganoderic and lucidenic acids-the activity of other compounds remains elusive. Here we show that ganodermanontriol (GDNT), a Ganoderma alcohol, specifically suppressed proliferation (anchorage-dependent growth) and colony formation (anchorage-independent growth) of highly invasive human breast cancer cells MDA-MB-231. GDNT suppressed expression of the cell cycle regulatory protein CDC20, which is over-expressed in precancerous and breast cancer cells compared to normal mammary epithelial cells. Moreover, we found that CDC20 is over-expressed in tumors when compared to the tissue surrounding the tumor in specimens from breast cancer patients. GDNT also inhibited invasive behavior (cell adhesion, cell migration, and cell invasion) through the suppression of secretion of urokinase-plasminogen activator (uPA) and inhibited expression of uPA receptor. In conclusion, mushroom GDNT is a natural agent that has potential as a therapy for invasive breast cancers.

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Available from: Andrej Jedinak, May 19, 2015
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    • "In concert with this finding, depleting endogenous Cdc20, which is frequently overexpressed in various cancer cell lines (Kidokoro et al., 2008), led to mitotic arrest followed by cell death (Huang et al., 2009). Consistently, Cdc20 was highly expressed in various types of human tumors (Jiang et al., 2011; Kato et al., 2012). These findings advocate for elevated Cdc20 expression as a possible prognostic marker and therapeutic target in treating various human cancers. "
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    ABSTRACT: Anaphase-promoting complex Cdc20 (APC(Cdc20)) plays pivotal roles in governing mitotic progression. By suppressing APC(Cdc20), antimitotic agents activate the spindle-assembly checkpoint and induce apoptosis after prolonged treatment, whereas depleting endogenous Cdc20 suppresses tumorigenesis in part by triggering mitotic arrest and subsequent apoptosis. However, the molecular mechanism(s) underlying apoptosis induced by Cdc20 abrogation remains poorly understood. Here, we report the BH3-only proapoptotic protein Bim as an APC(Cdc20) target, such that depletion of Cdc20 sensitizes cells to apoptotic stimuli. Strikingly, Cdc20 and multiple APC-core components were identified in a small interfering RNA screen that, upon knockdown, sensitizes otherwise resistant cancer cells to chemoradiation in a Bim-dependent manner. Consistently, human adult T cell leukemia cells that acquire elevated APC(Cdc20) activity via expressing the Tax viral oncoprotein exhibit reduced Bim levels and resistance to anticancer agents. These results reveal an important role for APC(Cdc20) in governing apoptosis, strengthening the rationale for developing specific Cdc20 inhibitors as effective anticancer agents.
    Full-text · Article · May 2014 · Developmental Cell
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    • "Recently Cdc20 overexpression has been associated with inappropriately functioning SAC and aneuploidization in oral cancer (Mondal et al, 2007). High Cdc20 expression has been reported in several human cancer cell lines (Kim et al, 2005b; Iacomino et al, 2006; Thirthagiri et al, 2007; Yuan et al, 2006; Jiang et al, 2011; Chang et al, 2012) and several carcinoma tissues (Kim et al, 2005b; Ouellet et al, 2006; Kidokoro et al, 2008; Jiang et al, 2011). High Cdc20 expression has also been linked to poor prognosis in lung (Kato et al, 2012), oral squamous cell (Moura et al, 2013), bladder (Choi et al, 2013), colon (Wu et al, 2013) and pancreatic (Chang et al, 2012) carcinomas. "
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    ABSTRACT: Background: Cdc20 is an essential component of cell division and responsible for anaphase initiation regulated by securin degradation. Cdc20 function is strongly regulated by the spindle assembly checkpoint to ensure the timely separation of sister chromatids and integrity of the genome. We present the first results on Cdc20 in a large clinical breast cancer material. Methods: The study was based on 445 breast cancer patients with up to 20 years of follow-up (mean 10.0 years). DNA content was determined by image cytometry on cell imprints, and Cdc20 and securin immunohistochemistry on tissue microarrays of breast cancer tissue. Results: In our results, high Cdc20 and securin expression was associated with aneuploid DNA content. In prognostic analyses, high Cdc20 immunoexpression alone and in combination with high securin immunoexpression indicated aggressive course of disease and up to 6.8-fold (P<0.001) risk of breast cancer death. Particularly, high Cdc20 and securin immunoexpression identified a patient subgroup with extremely short, on average 2.4 years, breast cancer survival and triple-negative breast cancer (TNBC) subtype. Conclusions: We report for the first time the association of high Cdc20 and securin immunoexpression with extremely poor outcome of breast cancer patients. Our experience indicates that Cdc20 and securin are promising candidates for clinical applications in breast cancer prognostication, especially in the challenging prognostic decisions of TNBC.
    Full-text · Article · May 2014 · British Journal of Cancer
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    • "So far, the anti-metastatic effect of ganoderiol is rarely reported. Only a pure compound, ganodermanontriol, was found to inhibit cell adhesion, migration and invasion by decreasing the secretion of uPA and downregulation of uPAR expression in MDA-MB-231 cells [45]. "
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    ABSTRACT: Cell adhesion, migration and invasion are critical steps for carcinogenesis and cancer metastasis. Ganoderma lucidum, also called Lingzhi in China, is a traditional Chinese medicine, which exhibits anti-proliferation, anti-inflammation and anti-metastasis properties. Herein, GAEE, G. lucidum extract mainly contains ganoderiol A (GA), dihydrogenated GA and GA isomer, was shown to inhibit the abilities of adhesion and migration, while have a slight influence on that of invasion in highly metastatic breast cancer MDA-MB-231 cells at non-toxic doses. Further investigation revealed that GAEE decreased the active forms of focal adhesion kinase (FAK) and disrupted the interaction between FAK and SRC, which lead to deactivating of paxillin. Moreover, GAEE treatment downregulated the expressions of RhoA, Rac1, and Cdc42, and decreased the interaction between neural Wiskott-Aldrich Syndrome protein (N-WASP) and Cdc42, which impair cell migration and actin assembly. To our knowledge, this is the first report to show that G.lucidum triterpenoids could suppress cell migration and adhesion through FAK-SRC-paxillin signaling pathway. Our study also suggests that GAEE may be a potential agent for treatment of breast cancer.
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