Monoterpene Glycoside ESK246 from Pittosporum Targets LAT3 Amino Acid Transport and Prostate Cancer Cell Growth

详细信息    查看全文

• 作者：Qian Wang ; Tanja Grkovic ; Josep Font ; Sarah Bonham ; Rebecca H Pouwer ; Charles G Bailey ; Anne M Moran ; Renae M Ryan ; John EJ Rasko ; Mika Jormakka ; Ronald J Quinn ; Jeff Holst
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：June 20, 2014
• 年：2014
• 卷：9
• 期：6
• 页码：1369-1376
• 全文大小：443K
• 年卷期：v.9,no.6(June 20, 2014)
• ISSN：1554-8937

文摘

The l-type amino acid transporter (LAT) family consists of four members (LAT1鈥?) that mediate uptake of neutral amino acids including leucine. Leucine is not only important as a building block for proteins, but plays a critical role in mTORC1 signaling leading to protein translation. As such, LAT family members are commonly upregulated in cancer in order to fuel increased protein translation and cell growth. To identify potential LAT-specific inhibitors, we established a function-based high-throughput screen using a prefractionated natural product library. We identified and purified two novel monoterpene glycosides, ESK242 and ESK246, sourced from a Queensland collection of the plant Pittosporum venulosum. Using Xenopus laevis oocytes expressing individual LAT family members, we demonstrated that ESK246 preferentially inhibits leucine transport via LAT3, while ESK242 inhibits both LAT1 and LAT3. We further show in LNCaP prostate cancer cells that ESK246 is a potent (IC₅₀ = 8.12 渭M) inhibitor of leucine uptake, leading to reduced mTORC1 signaling, cell cycle protein expression and cell proliferation. Our study suggests that ESK246 is a LAT3 inhibitor that can be used to study LAT3 function and upon which new antiprostate cancer therapies may be based.