Using a biologically annotated library to analyze the anticancer mechanism of serine palmitoyl transferase (SPT) inhibitors

Sano, Osamu; Kazetani, Ken-ichi; Adachi, Ryutaro; Kurasawa, Osamu; Kawamoto, Takahiro; Iwata, Hidehisa

doi:10.1002/2211-5463.12196

Cited by 8 publications

(5 citation statements)

References 32 publications

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“…The biologically annotated compound library was composed of about 6400 small molecules, selected based on their biological diversity [ 27 ]. The library contained bioactive compounds with 50% inhibitory concentration (IC 50 ) or half-maximal response values (EC 50 ) less than 1 μM on diverse targets in the internal/external databases, as well as commercially available sets of known pharmacologically active compounds.…”

Section: Methodsmentioning

confidence: 99%

Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition

et al. 2017

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Elucidating the bioactive compound modes of action is crucial for increasing success rates in drug development. For anticancer drugs, defining effective drug combinations that overcome resistance improves therapeutic efficacy. Herein, by using a biologically annotated compound library, we performed a large-scale combination screening with Stearoyl-CoA desaturase-1 (SCD1) inhibitor, T-3764518, which partially inhibits colorectal cancer cell proliferation. T-3764518 induced phosphorylation and activation of AMPK in HCT-116 cells, which led to blockade of downstream fatty acid synthesis and acceleration of autophagy. Attenuation of fatty acid synthesis by small molecules suppressed the growth inhibitory effect of T-3764518. In contrast, combination of T-3764518 with autophagy flux inhibitors synergistically inhibited cellular proliferation. Experiments using SCD1 knock-out cells validated the results obtained with T-3764518. The results of our study indicated that activation of autophagy serves as a survival signal when SCD1 is inhibited in HCT-116 cells. Furthermore, these findings suggest that combining SCD1 inhibitor with autophagy inhibitors is a promising anticancer therapy.

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Section: Methodsmentioning

confidence: 99%

Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition

et al. 2017

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“…Specific sphingolipid synthesis inhibitors are now being evaluated in preclinical and early-phase clinical trials as anticancer agents. Myriocin, a serine palmitoyltransferase (SPT) inhibitor, reduces proliferation of lung cancer and melanoma cell lines 137 and attenuates HCC in mice 118 . Furthermore, the SPHK2 inhibitor ABC294640 is in clinical trials for cholangiocarcinoma 138 , multiple myeloma 139 and advanced HCC 140 (Table 1).…”

Section: Lipid Metabolismmentioning

confidence: 99%

mTOR signalling and cellular metabolism are mutual determinants in cancer

2018

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Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy. rapamycin treatment. Activation of mTORC1 by growth factors and nutrientsThe activation of mTORC1 is dependent on nutrients and growth factors. In response to nutrients, mTORC1 translocates from the cytoplasm to the lysosomal surface, where it is activated by growth factors via PI3K-AKT signalling. Growth factors, for instance, insulin, activate AKT4 via a cognate receptor, phosphoinositide-dependent kinase 1 (PDK1) and PI3K (Fig. 1). AKT inhibits the TSC1-TSC2 complex5, which is a GTPase-activating protein (GAP) for the small GTPase RHEB6. GTP-bound RHEB directly binds and activates mTORC1 at the lysosome 7,8 (Fig. 1). Nutrient-induced lysosomal translocation of mTORC1Nutrients, in particular amino acids, promote lysosomal localization of mTORC1 via the RAS-related GTP-binding proteins (RAGs) 9 , thereby enabling mTORC1 to encounter RHEB. RAGs are small GTPases that form obligate heterodimers. RAGA or RAGB associates with RAGC or RAGD. In the active state, GTP-bound RAGA or RAGB and GDP-bound RAGC or RAGD bind RAPTOR and thereby recruit mTORC1 to the lysosomal surface. The nucleotide binding status of the RAGs is tightly regulated by amino acids 9 obtained from intracellular synthesis, protein turnover or extracellular sources via specific transporters (Fig. 1; for details, see following sections). Among the amino acids, leucine, arginine and glutamine are the most effective activators of mTORC1. Leucine and arginine bind to sestrin 2 and CASTOR1, respectively, ultimately to activate the RAGs and mTORC1 (for details, see Fig. 1, ref. 10 and references therein). The lysosomal amino acid transporter SLC38A9 promotes mTORC1 activation by exporting essential amino acids to the cytoplasm 11 , where, for example, leucine can bind sestrin 2. Leucine export is stimulated by arginine binding to SLC38A9 (ref. 11 ). Glutamine activates RAGs by promoting glutaminolysis. During glutaminolysis, glutaminase (GLS) and glutamate dehydrogenase (GDH) convert glutamine to αketoglutarate (αKG), which ultimately activates mTORC1 via prolyl hydroxylases (PHDs) by promoting GTP loading of RAGB12 (Fig. 1). Leucine also stimulates αKG production by directly binding and allosterically activating GDH. Furthermore, glutamine activates mTORC1 independently of RAGs via the small GTPase ADPri...

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“…Recently, the results of several medicinal chemistry campaigns against SPT have been reported. 176 – 179 Using high-throughput screening, Genin and colleagues discovered imidazopyridine and pyrazolylpiperidine based compounds as inhibitors of SPT. 176 In vitro imidazopyridine had an IC 50 of 5 nM against microsomal human SPT whilst pyrazolylpiperidine gave an IC 50 of 64 nM.…”

Section: Serine Palmitoyltransferase (Spt)mentioning

confidence: 99%

“…More detailed analysis of the mechanism of action revealed that SPT inhibition resulted in an up-regulation of COX-2 expression leading to cell death. 179 The publication of these results suggest that SPT is a potent and viable target for novel therapeutics.…”

Section: Serine Palmitoyltransferase (Spt)mentioning

confidence: 99%