Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Abstract

Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTEN-deficient B cell lymphoma cells, and displayed 2 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 regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.

Keywords:

• diffuse large B cell lymphoma
• natural compounds
• mTOR-AKT signaling
• schweinfurthins
• trans-Golgi-network

Author Contributions

X.B., W.Z., Q.X., J.W., Y.T., T.U. and K.N. conceived and designed the study. X.B, W.Z., N.H.S., K.L.A., Q.X., K.T., Z.W., W.L., L.P., H.C., W.L., Y.S., N.T., Z.D., H.D., and Y.K. acquired and analyzed data. X.B., W.Z., N.Z., M.W.J., M.P., and K.N. wrote the paper. D.G.I.K. provided material support.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The paper is dedicated to the memory of Jue-Lon Shie. We thank Drs. Hiroyuki Arai and Tomohiko Taguchi at University of Tokyo for providing the plasmids encoding human ORP family proteins. We gratefully acknowledge technical support, discussion and comments from Bruce Littlefield, Tina Watanabe, May Chin, Christine Kitsos, Guobing Miao, Dayong Qiu, Karen Ackermann, Kuan-chun Huang, Hiroyuki Katayama, Lei Wang, Jesse Chow, Yasuhiro Funahashi, Junji Matsui, Akihiko Tsuruoka, Yoshiya Oda, Takashi Owa and Kentaro Yoshimatsu of Eisai Product Creation Systems.

Funding

The isolation of natural schweinfurthins in Dr. Kingston's lab was supported by the NIH under Cooperative Agreement U01 TW000313 with the International Cooperative Biodiversity Groups.

Supplemental Material

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