期刊
ACS CHEMICAL BIOLOGY
卷 9, 期 6, 页码 1369-1376出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb500120x
关键词
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资金
- Movember through Prostate Cancer Foundation of Australia [YI0813, PG2910, YI0707]
- Australian Movember Revolutionary Team Award Targeting Advanced Prostate Cancer
- National Breast Cancer Foundation [ECF-12-05]
- National Health and Medical Research Council [1051820, 1035693, 1048784, 571093]
- Cure the Future
- Tour de Cure Fellowship
- Queensland Government Smart Futures NIRAP program
- Australian Research Council [LE0668477, LE0237908]
- Compounds Australia from the Queensland Government Smart State Research Facilities Fund
- Australian Government under the Super Science Initiative
- Education Investment Fund
- National Breast Cancer Foundation [ECF-12-05] Funding Source: researchfish
The L-type amino acid transporter (LAT) family consists of four members (LAT1-4) 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 mu 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.
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