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

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.

• Authors: Leyre Brizuela, Audrey Dayon, Nicolas Doumerc, Isabelle Ader, Muriel Golzio, Jean-Claude Izard, Yukihiko Hara, Bernard Malavaud, Olivier Cuvillier
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 24 Issue 10 Pg. 3882-94 (Oct 2010) ISSN: 1530-6860 [Electronic] United States
• PMID: 20522783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tea
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase

Topics

• Humans
• Male
• Phosphotransferases (Alcohol Group Acceptor) (physiology)
• Prostatic Neoplasms (pathology)
• Tea (chemistry)
• Wine (analysis)