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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/10468
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| Title: | Overexpressed fatty acid synthase in gastrointestinal stromal tumors: Targeting a progression-associated metabolic driver enhances the antitumor effect of imatinib |
| Authors: | Li, CF;Fang, FM;Chen, YY;Liu, TT;Chan, TC;Yu, SC;Chen, LT;Huang, HY |
| Contributors: | National Institute of Cancer Research |
| Abstract: | Purpose: In gastrointestinal stromal tumors (GISTs), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN). Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNA interference or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivo. Results:FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (p<0.0001). FASN overexpression was associated with a nongastric location (p = 0.05), unfavorable genotype (p=0.005), and increased risk level (p<0.001) and independently predicted shorter disease-free survival (p<0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and re-sensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RSP6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT, Ki-67, and phosphorylated PIK3/AKT/mTOR levels and increased TUNEL labeling. Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. |
| Date: | 2017-08 |
| Relation: | Clinical Cancer Research. 2017 Aug;23(16):4908-4918. |
| Link to: | http://dx.doi.org/10.1158/1078-0432.ccr-16-2770 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-0432&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000407614400039 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85028058125 |
| Appears in Collections: | [陳立宗] 期刊論文
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| PUB28442505.pdf | | 2645Kb | Adobe PDF | 193 | View/Open |
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