Triterpenes From Ganoderma Lucidum Induce Autophagy in Colon Cancer Through the Inhibition of p38 Mitogen-Activated Kinase (p38 MAPK)

Methodist Research Institute, Indianapolis, Indiana, USA.
Nutrition and Cancer (Impact Factor: 2.32). 06/2010; 62(5):630-40. DOI: 10.1080/01635580903532390
Source: PubMed


Medicinal mushroom Ganoderma lucidum is one of the most esteemed natural products that have been used in the traditional Chinese medicine. In this article, we demonstrate that G. lucidum triterpene extract (GLT) suppresses proliferation of human colon cancer cells HT-29 and inhibits tumor growth in a xenograft model of colon cancer. These effects of GLT are associated with the cell cycle arrest at G0/G1 and the induction of the programmed cell death Type II-autophagy in colon cancer cells. Here, we show that GLT induces formation of autophagic vacuoles and upregulates expression of Beclin-1 (1.3-fold increase) and LC-3 (7.3-fold increase) proteins in colon cancer cells and in tumors in a xenograft model (Beclin-1, 3.9-fold increase; LC-3, 1.9-fold increase). Autophagy is mediated through the inhibition of p38 mitogen-activated protein kinase (p38 MAPK) because p38 MAPK inhibitor, SB202190, induces autophagy and expression of Beclin-1 (1.2-fold increase) and LC-3 (7.4-fold increase), and GLT suppresses phosphorylation of p38 MAPK ( approximately 60% inhibition) in colon cancer cells. Taken together, our data demonstrate a novel mechanism responsible for the inhibition of colon cancer cells by G. lucidum and suggest GLT as natural product for the treatment of colon cancer.

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Available from: Andrej Jedinak, May 19, 2015
    • "No side effects were observed on renal, hepatic, and hematological parameters (Hsu et al., 2008). Furthermore, studies on the human colon cancer cell line HT-29 showed that triterpenes from G. lucidum induced cell cycle arrest in the G0/G1 phase and the formation of autophagic vacuoles (Thyagarajan et al., 2010). The study by Liang et al. (2014) evaluated the effect of G. lucidum polysaccharides (GLP) on human colon cancer cells (HCT-116 cell line). "
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    ABSTRACT: The genus Ganoderma includes about 80 species growing on cut or rotten trees. The most commonly used species is Ganoderma ludicum. Biomolecules responsible for the health benefits of Ganoderma are polysaccharides with an immunostimulative effect and triterpenes with a cytotoxic action. For more than 2000 years, it has been used traditionally in the treatment of various pathological conditions and recently, its immunoregulatory, antiviral, antibacterial, antioxidant, hepatoprotective, and anticancer potential has been confirmed. A wide range of Ganoderma extracts and preparations arrest the cell cycle in different phases and consequently inhibit the growth of various types of cancer cells. Extracts containing polysaccharides stimulate immunological reactions through the production of various cytokines and mobilization of immune system cells. In-vivo studies have confirmed the anticancer potential and the antimetastatic effects of compounds originating from Ganoderma. There is also evidence for the chemopreventive action of Ganoderma extracts in bladder, prostate, liver, and breast cancer. The results of clinical studies suggest the combined use of G. lucidum with conventional chemotherapy/radiotherapy, but the methodology and the results of these studies are being questioned. Therefore, a constant need for new clinical trials exists.
    No preview · Article · Aug 2015 · European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP)
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    • "EORP has been shown to inhibit LPS-induced inflammatory cytokine in murine RAW264.7 cells by suppression of the phosphorylation of ERK1/2 and JNK [22]. Active lipids of Ganoderma lucidum spores are able to enhance apoptosis in THP-1 cells through inhibition of ERK1/2 and Akt and activation of JNK1/2 signaling pathways [32], whereas triterpenes from Ganoderma lucidum induce autophagy in colon cancer through the inhibition of P38 MAPK [37]. Our previous studies showed that EORP reduces LPS-induced the ICAM-1 expression by the decrease of ERK1/2 activation [27], and prevents the PDGF-stimulated HASMCs proliferation through inhibition of JNK activation [32]. "
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    ABSTRACT: The expression of inflammatory cytokines on vascular walls is a critical event in vascular diseases and inflammation. The aim of the present study was to examine the effects of an extract of Ganoderma lucidum (Reishi) polysaccharides (EORPs), which is effective against immunological disorders, on interleukin- (IL-) 1 β expression by human aortic smooth muscle cells (HASMCs) and the underlying mechanism. The lipopolysaccharide- (LPS-) induced IL-1 β expression was significantly reduced when HASMCs were pretreated with EORP by Western blot and immunofluorescent staining. Pretreatment with 10 μ g/mL EORP decreased LPS-induced ERK, p38, JNK, and Akt phosphorylation. But the increase in IL-1 β expression with LPS treatment was only inhibited by pretreatment with the ERK1/2 inhibitor, while the JNK and p38 inhibitors had no effect. In addition, EORP reduced the phosphorylation and nuclear translocation of nuclear factor- (NF-) κ B p65 in LPS-treated HASMCs. Furthermore, in vivo, IL-1 β expression was strongly expressed in thoracic aortas in LPS-treated mice. Oral administration of EORP decreased IL-1 β expression. The level of IL-1 β expression in LPS-treated or in LPS/EORP-treated group was very low and was similar to that of the saline-treated group in toll-like receptor 4-deficient (TLR4(-/-)) mice. These findings suggest that EORP has the anti-inflammatory property and could prove useful in the prevention of vascular diseases and inflammatory responses.
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    • "Two major signaling regulatory pathways are involved in autophagy initiation: Akt/mammalian target of rapamycin (mTOR) pathway and mitogen-activated protein kinase (MAPK) pathway. Rhodiola rosea extracts and 6- Shogaol (5) have been described to mediate autophagy through inhibition of Akt/mTOR pathway in bladder cancer cell lines and in A549 human nonsmall cell lung cancer cells, respectively, while triterpenes from Ganoderma Lucidum induced autophagy in colon cancer cells through the inhibition of p38 mitogen-activated kinase (p38 MAPK) pathway (Hung et al. 2009; Liu et al. 2012; Thyagarajan et al. 2010). Autophagy is taking over its death function preferentially in situations when crucial apoptotic modulators such as Bax and Bak are missing and also in caspase-defective cells (Fazi et al. 2008; Kondo et al. 2005). "
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    ABSTRACT: Over the past decades, apoptosis emerged as a leading strategy to eliminate cancer cells. Nowadays, it becomes progressively clear that apoptosis is not the only programmed cell death mechanism implicated in the elimination of malignant cells. This review will discuss non-apoptotic cell death modalities and will focus on natural compounds acting as inducers of these recently described processes. We will describe the major molecular characteristics of each individual death mechanism and we will detail the effects of natural and naturally-derived compounds on these cellular mechanisms.
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