Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways
Seong M. Kim, … , Stephen Hanessian, Aimee L. Edinger
Seong M. Kim, … , Stephen Hanessian, Aimee L. Edinger
Published September 26, 2016
Citation Information: J Clin Invest. 2016;126(11):4088-4102. https://doi.org/10.1172/JCI87148.
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Research Article Cell biology Metabolism

Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

Abstract

Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways. SH-BC-893 activated protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve. The concomitant mislocalization of the PIKfyve product PI(3,5)P2 triggered cytosolic vacuolation and blocked lysosomal fusion reactions essential for LDL, autophagosome, and macropinosome degradation. By simultaneously limiting access to both extracellular and intracellular nutrients, SH-BC-893 selectively killed cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo. However, slower-growing, autochthonous PTEN-deficient prostate tumors that did not exhibit a classic Warburg phenotype were equally sensitive. Remarkably, normal proliferative tissues were unaffected by doses of SH-BC-893 that profoundly inhibited tumor growth. These studies demonstrate that simultaneously blocking parallel nutrient access pathways with sphingolipid-based drugs is broadly effective and cancer selective, suggesting a potential strategy for overcoming the resistance conferred by tumor heterogeneity.

Authors

Seong M. Kim, Saurabh G. Roy, Bin Chen, Tiffany M. Nguyen, Ryan J. McMonigle, Alison N. McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T. Finicle, Tricia T. Nguyen, Archna Ravi, Manuel U. Ramirez, Tim Wiher, Garret G. Guenther, Mari Kono, Atsuo T. Sasaki, Lois S. Weisman, Eric O. Potma, Bruce J. Tromberg, Robert A. Edwards, Stephen Hanessian, Aimee L. Edinger

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Figure 1

SH-BC-893 triggers nutrient transporter internalization mimicking starvation.

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SH-BC-893 triggers nutrient transporter internalization mimicking starva...
(A) Structures of FTY720 and SH-BC-893. (B) S1P1 receptor–driven GFP expression measured by flow cytometry in reporter MEFs after a 24-hour incubation with the indicated compounds at 2.5 μM. 893, SH-BC-893; 893-P, (SH-BC-893-phosphate); FTY720-P, (FTY720-phosphate). (C) Surface 4F2HC measured by flow cytometry in FL5.12 cells treated with 5 μM FTY720 or SH-BC-893 or 10 μM C2-ceramide. (D) SH-BC-893–treated SW620 cells stained as indicated. Scale bar: 10 μm. (E) Viability of BCLXL-overexpressing FL5.12 cells treated as indicated, with or without 5.5 mM methyl pyruvate or 2 mM dimethyl α-ketoglutarate (α-KG). (F) Bound NADH fraction in MEFs treated with mitochondrial inhibitors (1 μM oligomycin or 1 μM rotenone and antimycin A [Rot/AA]), 1 mM 2-DG, 5 μM FTY720, or 7.5 μM SH-BC-893 for 16 hours. For starvation, growth media were replaced with DMEM lacking glucose and amino acids, supplemented with 10% dialyzed FCS. Statistical significance was compared with respective controls. (G) Oxygen consumption rate (OCR) in MEFs treated with FTY720 or SH-BC-893 for 16 hours measured by an XF24 Extracellular Flux Analyzer (Seahorse Bioscience). Error bars indicate the mean ± SEM. *P <0.05, **P < 0.01, and ***P <0.001, by unpaired, 2-tailed Student’s t test. P values were determined using Tukey’s method when correcting for multiple comparisons. Data are representative of at least 3 independent experiments.