Overexpressed Fatty Acid Synthase in Gastrointestinal Stromal Tumors: Targeting a Progression-Associated Metabolic Driver Enhances the Antitumor Effect of Imatinib

被引:33
作者
Li, Chien-Feng [1 ,2 ,3 ,4 ]
Fang, Fu-Min [5 ,6 ]
Chen, Yen-Yang [6 ,7 ]
Liu, Ting-Ting [6 ,8 ]
Chan, Ti-Chun [1 ]
Yu, Shih-Chen [6 ,8 ]
Chen, Li-Tzong [2 ]
Huang, Hsuan-Ying [6 ,8 ]
机构
[1] Chi Mei Med Ctr, Dept Pathol, Tainan, Taiwan
[2] Natl Hlth Res Inst, Natl Inst Canc Res, Tainan, Taiwan
[3] Southern Taiwan Univ Sci & Technol, Dept Biotechnol, Tainan, Taiwan
[4] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Pathol, Kaohsiung, Taiwan
[5] Kaohsiung Chang Gung Mem Hosp, Dept Radiat Oncol, Kaohsiung, Taiwan
[6] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan
[7] Kaohsiung Chang Gung Mem Hosp, Dept Internal Med, Div Oncol, Kaohsiung, Taiwan
[8] Kaohsiung Chang Gung Mem Hosp, Dept Pathol, Kaohsiung, Taiwan
关键词
BREAST-CANCER CELLS; THERAPEUTIC TARGET; KIT; RESISTANCE; INHIBITION; APOPTOSIS; AUTOPHAGY; TRANSCRIPTION; SUPPRESSES; EXPRESSION;
D O I
10.1158/1078-0432.CCR-16-2770
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: In gastrointestinal stromal tumors (GIST), 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 RNAi 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 knock-down inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized 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/RPS6/4E-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 phosphorylation, Ki-67, and phosphorylated PI3K/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. (C) 2017 AACR.
引用
收藏
页码:4908 / 4918
页数:11
相关论文
共 34 条
[1]   Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation [J].
Antonescu, CR ;
Besmer, P ;
Guo, TH ;
Arkun, K ;
Hom, G ;
Koryotowski, B ;
Leversha, MA ;
Jeffrey, PD ;
Desantis, D ;
Singer, S ;
Brennan, MF ;
Maki, RG ;
DeMatteo, RP .
CLINICAL CANCER RESEARCH, 2005, 11 (11) :4182-4190
[2]   KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway [J].
Bauer, S. ;
Duensing, A. ;
Demetri, G. D. ;
Fletcher, J. A. .
ONCOGENE, 2007, 26 (54) :7560-7568
[3]   Diacylglycerol Metabolism and Signaling Is a Driving Force Underlying FASN Inhibitor Sensitivity in Cancer Cells [J].
Benjamin, Daniel I. ;
Li, Daniel S. ;
Lowe, Wallace ;
Heuer, Timothy ;
Kemble, George ;
Nomura, Daniel K. .
ACS CHEMICAL BIOLOGY, 2015, 10 (07) :1616-1623
[4]   Increased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma [J].
Calvisi, Diego F. ;
Wang, Chunmei ;
Ho, Coral ;
Ladu, Sara ;
Lee, Susie A. ;
Mattu, Sandra ;
Destefanis, Giulia ;
Delogu, Salvatore ;
Zimmermann, Antje ;
Ericsson, Johan ;
Brozzetti, Stefania ;
Staniscia, Tommaso ;
Chen, Xin ;
Dombrowski, Frank ;
Evert, Matthias .
GASTROENTEROLOGY, 2011, 140 (03) :1071-U542
[5]   4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic Acid (C75), an Inhibitor of Fatty-acid Synthase, Suppresses the Mitochondrial Fatty Acid Synthesis Pathway and Impairs Mitochondrial Function [J].
Chen, Cong ;
Han, Xiao ;
Zou, Xuan ;
Li, Yuan ;
Yang, Liang ;
Cao, Ke ;
Xu, Jie ;
Long, Jiangang ;
Liu, Jiankang ;
Feng, Zhihui .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (24) :17184-17194
[6]   Autophagy is a therapeutic target in anticancer drug resistance [J].
Chen, Suning ;
Rehman, Sumaiyah K. ;
Zhang, Wei ;
Wen, Aidong ;
Yao, Libo ;
Zhang, Jian .
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 2010, 1806 (02) :220-229
[7]  
Demetri GD, 2010, J NATL COMPR CANC NE, V8, pS1
[8]  
Flavin R, 2010, FUTURE ONCOL, V6, P551, DOI [10.2217/fon.10.11, 10.2217/FON.10.11]
[9]   Diagnosis of gastrointestinal stromal tumors: A consensus approach [J].
Fletcher, CDM ;
Berman, JJ ;
Corless, C ;
Gorstein, F ;
Lasota, J ;
Longley, BJ ;
Miettinen, M ;
O'Leary, TJ ;
Remotti, H ;
Rubin, BP ;
Shmookler, B ;
Sobin, LH ;
Weiss, SW .
HUMAN PATHOLOGY, 2002, 33 (05) :459-465
[10]   Quadruple-Negative GIST Is a Sentinel for Unrecognized Neurofibromatosis Type 1 Syndrome [J].
Gasparotto, Daniela ;
Rossi, Sabrina ;
Polano, Maurizio ;
Tamborini, Elena ;
Lorenzetto, Erica ;
Sbaraglia, Marta ;
Mondello, Alessia ;
Massani, Marco ;
Lamon, Stefano ;
Bracci, Raffaella ;
Mandolesi, Alessandra ;
Frate, Elisabetta ;
Stanzial, Franco ;
Agaj, Jerin ;
Mazzoleni, Guido ;
Pilotti, Silvana ;
Gronchi, Alessandro ;
Dei Tos, Angelo Paolo ;
Maestro, Roberta .
CLINICAL CANCER RESEARCH, 2017, 23 (01) :273-282