Natural Sphingadienes Inhibit Akt-Dependent Signaling and Prevent Intestinal Tumorigenesis

Abstract

Sphingolipid metabolites regulate cell proliferation, migration, and stress responses. Alterations in sphingolipid metabolism have been proposed to contribute to carcinogenesis, cancer progression, and drug resistance. We identified a family of natural sphingolipids called sphingadienes and investigated their effects in colon cancer. We find that sphingadienes induce colon cancer cell death in vitro and prevent intestinal tumorigenesis in vivo. Sphingadienes exert their influence by blocking Akt translocation from the cytosol to the membrane, thereby inhibiting protein translation and promoting apoptosis and autophagy. Sphingadienes are orally available, are slowly metabolized through the sphingolipid degradative pathway, and show limited short-term toxicity. Thus, sphingadienes represent a new class of therapeutic and/or chemopreventive agents that blocks Akt signaling in neoplastic and preneoplastic cells. [Cancer Res 2009;69(24):9457-64]

Sphingosine Kinases Are Not Required for Inflammatory Responses in Macrophages

“…Previous work pointed out the importance of sphingolipids in the regulation of autophagy (56 -58). Indeed, manipulation of sphingolipid metabolic enzymes modulates autophagy in various systems (22,34,49,(52)(53)(54). We speculate that pharmacologic inhibition of Sphk isoenzymes could lead to intracellular sphingolipid accumulation and compensatory autophagic responses in cells with high flux in the sphingolipid metabolic pathways.…”

Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs

“…We next asked whether it was possible to reverse SPL downregulation in the gut, thus making it a potential target for chemoprevention. We recently reported the chemopreventive activity of SDs, compounds derived from the metabolism of sphingolipids in soy and other nonmammalian food sources (32,33). SDs are cytotoxic to colon cancer cells and reduce adenoma formation when administered orally to Apc Min/+ mice (32,33).…”

“…We recently reported the chemopreventive activity of SDs, compounds derived from the metabolism of sphingolipids in soy and other nonmammalian food sources (32,33). SDs are cytotoxic to colon cancer cells and reduce adenoma formation when administered orally to Apc Min/+ mice (32,33). To address the effects of SDs in colitis, we evaluated colon S1P levels in WT mice treated with 25 mg/kg SD (or vehicle alone) by gavage for 6 days.…”

Effects on inflammatory responses by the sphingoid base 4,8-sphingadienine

“…It is unknown what portion of 4,8-SD becomes bioavailable in the mucosal cells of the intestines after ingestion of complex SLs. However, it was reported that sphingadienines in general have the advantage over other SLs of being slowly metabolized and of having a long half-life in intestinal epithelial cells (21).…”