Article

The sphingosine kinase-1 survival pathway is a molecular target for the tumor-suppressive tea and wine polyphenols in prostate cancer

Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
The FASEB Journal (Impact Factor: 5.48). 10/2010; 24(10):3882-94. DOI: 10.1096/fj.10-160838
Source: PubMed

ABSTRACT The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway has been associated with cancer promotion and progression and resistance to treatments in a number of cancers, including prostate adenocarcinoma. Here we provide the first evidence that dietary agents, namely, epigallocatechin gallate (EGCg, IC(50)≈75 μM), resveratrol (IC(50)≈40 μM), or a mixture of polyphenols from green tea [polyphenon E (PPE), IC(50)≈70 μM] or grapevine extract (vineatrol, IC(50)≈30 μM), impede prostate cancer cell growth in vitro and in vivo by inhibiting the SphK1/S1P pathway. We establish that SphK1 is a downstream effector of the ERK/phospholipase D (PLD) pathway, which is inhibited by green tea and wine polyphenols. Enforced expression of SphK1 impaired the ability of green tea and wine polyphenols, as well as pharmacological inhibitors of PLD and ERK activities, to induce apoptosis in PC-3 and C4-2B cells. The therapeutic efficacy of these polyphenols on tumor growth and the SphK1/S1P pathway were confirmed in animals using a heterotopic PC-3 tumor in place model. PC-3/SphK1 cells implanted in animals developed larger tumors and resistance to treatment with polyphenols. Furthermore, using an orthotopic PC-3/GFP model, the chemopreventive effect of an EGCg or PPE diet was associated with SphK1 inhibition, a decrease in primary tumor volume, and occurrence and number of metastases. These results provide the first demonstration that the prosurvival, antiapoptotic SphK1/S1P pathway represents a target of dietary green tea and wine polyphenols in cancer.

1 Follower
 · 
77 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: In addition to thousands of research papers related to resveratrol (RSV), approximated 300 review articles have been published. Earlier research tended to focus on pharmacological activities of RSV related to cardiovascular systems, inflammation, and carcinogenesis/cancer development. More recently, the horizon has been broadened by exploring the potential effect of RSV on the aging process, diabetes, neurological dysfunction, etc. Herein, we primarily focus on the in vivo pharmacological effects of RSV reported over the past 5 years (2009-2014). In addition, recent clinical intervention studies performed with resveratrol are summarized. Some discrepancies exist between in vivo studies with animals and clinical studies, or between clinical studies, which are likely due to disparate doses of RSV, experimental settings, and subject variation. Nevertheless, many positive indications have been reported with mammals, so it is reasonable to advocate for the conduct of more definitive clinical studies. Since the safety profile is pristine, an added advantage is the use of RSV as a dietary supplement. This article is part of a Special Issue entitled: Resveratol: Challenges in translating pre-clincial findigns to iproved patient outcomes. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 01/2015; DOI:10.1016/j.bbadis.2015.01.014 · 5.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell migration is a critical step in the progression of prostate cancer to the metastatic state, the lethal form of the disease. The anti-diabetic drug metformin has been shown to display anti-tumoral properties in prostate cancer cell and animal models, however, its role in the formation of metastases remains poorly documented. Here, we show that metformin reduces the formation of metastases to fewer solid organs in an orthotopic metastatic prostate cancer cell model established in nude mice. As predicted, metformin hampers cell motility in PC3 and DU145 prostate cancer cells and triggers a radical reorganization of the cell cytoskeleton. The small GTPase Rac1 is a master regulator of cytoskeleton organization and cell migration. We report that metformin leads to a major inhibition of Rac1 GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex1 (a Guanine nucleotide exchange factor and activator of Rac1), cAMP and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1, or P-Rex as well as the inhibition of the adenylate cyclase were able to reverse the anti-migratory effects of metformin. These results establish a novel mechanism of action for metformin and highlight its potential anti-metastatic properties in prostate cancer. Copyright © 2014, American Association for Cancer Research.
    Molecular Cancer Therapeutics 12/2014; DOI:10.1158/1535-7163.MCT-14-0102 · 6.11 Impact Factor
  • Source
    05/2014; 2(Suppl 1):O24. DOI:10.1186/2049-3002-2-S1-O24

Full-text

Download
6 Downloads
Available from
Jun 25, 2014