LAUSR

Schweinfurthins, a class of natural products, have attracted considerable interest for novel therapy development because of their selective and potent anti-proliferative activity against human cancer cells. However, the underlying mechanism is not well understood. Herein, we demonstrated that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Intracellularly, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, likely by binding to oxysterol-binding proteins, leading to an effective inhibition of mTOR/AKT signaling through inducing endoplasmic reticulum stress and suppressing both lipid raft-mediated PI3K activation and mTOR/RheB complex formation. Moreover, schweinfurthins were found to be highly potent toward PTEN-deficient B cell lymphoma cells, and displayed two orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in trans-Golgi-network trafficking and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest a new opportunity to modulate oncogenic signaling by interfering with TGN trafficking to treat mTOR/AKT-dependent human cancers.