Monoterpene glycoside ESK246 from Pittosporum targets LAT3 amino acid transport and prostate cancer cell growth.
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 μM) 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.
Origins of Cancer Laboratory and ‡Gene & Stem Cell Therapy Program, Centenary Institute , Camperdown NSW 2050, Australia.
Qian
Q
Wang
Tanja
T
Grkovic
Josep
J
Font
Sarah
S
Bonham
Rebecca H
RH
Pouwer
Charles G
CG
Bailey
Anne M
AM
Moran
Renae M
RM
Ryan
John E J
JE
Rasko
Mika
M
Jormakka
Ronald J
RJ
Quinn
Jeff
J
Holst
D026923:Amino Acid Transport Systems, Basic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006027:Glycosides / Q000494:pharmacology*; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000737:chemistry* / Q000378:metabolism; D007930:Leucine / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D039821:Monoterpenes / Q000737:chemistry* / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019685:Rosales / Q000737:chemistry*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism
D026923:Amino Acid Transport Systems, Basic; D000970:Antineoplastic Agents; C000600629:ESK242; C000600628:ESK246; D006027:Glycosides; D027283:Large Neutral Amino Acid-Transporter 1; D039821:Monoterpenes; D046912:Multiprotein Complexes; C469951:SLC7A6 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine