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.
    Developmental Cell 05/2014; 29(4):377-91. DOI:10.1016/j.devcel.2014.04.022 · 9.71 Impact Factor
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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.
    PLoS ONE 10/2013; 8(10):e76620. DOI:10.1371/journal.pone.0076620 · 3.23 Impact Factor
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    • "CDC20 is a protein regulating spindle checkpoint controlling the mitotic chromosome segregation during cell proliferation, which has been recently suggested as a potential therapeutic target [19], [20]. Indeed, the overexpression of CDC20 was demonstrated in breast cancer cell lines and primary breast tumors but not in normal mammary epithelial cells or breast tissues [19], [21], [22]. Therefore, NAHA suppresses growth of breast cancer cells through the down-regulation of expression of CDC20. "
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    ABSTRACT: We have recently synthesized novel N-alkylated amino acid-derived hydroxamate, 2-[Benzyl-(2-nitro-benzenesulfonyl)-amino]-N-hydroxy-3-methyl-N-propyl-butyramide (NAHA). Here, we evaluate the anticancer activity of NAHA against highly invasive human breast cancer cells MDA-MB-231 in vitro and in vivo. Cell growth was evaluated by MTT and soft agar assays. Protein expression was determined by DNA microarray and Western blot analysis. Metastatic potential was evaluated by cell adhesion, migration, invasion, capillary morphogenesis, and ELISA assays. The anticancer activity in vivo was evaluated in mouse xenograft model. NAHA inhibited proliferation and colony formation of MDA-MB-231 cells together with the down-regulation of expression of Cdk2 and CDC20 proteins. NAHA inhibited cell adhesion, migration, and invasion through the suppression of secretion of uPA. NAHA suppressed secretion of VEGF from MDA-MB-231 cells and inhibited capillary morphogenesis of human aortic endothelial cells (HAECs). Finally, NAHA at 50 mg/kg was not toxic and decreased tumor volume and tumor weight in vivo. This suppression of tumor growth was associated with the inhibition of mitotic figures and induction of apoptosis, and the reduction of CD31 and VEGF positive cells in tumors. NAHA could be a novel promising compound for the development of new drugs for the therapy of invasive breast cancers.
    PLoS ONE 03/2012; 7(3):e34283. DOI:10.1371/journal.pone.0034283 · 3.23 Impact Factor
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