[en] [en] BACKGROUND & AIMS: Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. Acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is an acetyl-enzyme A synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the nonselective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.
METHODS: Clinical significance of ACSS2 was analyzed using samples from patients with pancreatic cancer. ACSS2-knockout cells were established using the clustered regularly interspaced short palindromic repeats-associated protein 9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. The macropinocytotic index was evaluated by dextran uptake assay. Chromatin immunoprecipitation assay was performed to validate transcriptional activation. ACSS2-mediated tumor progression and muscle wasting were examined in orthotopic xenograft models.
RESULTS: Metabolic stress induced ACSS2 expression, which is associated with worse prognosis in pancreatic cancer. ACSS2 knockout significantly suppressed cell proliferation in 2-dimensional and 3-dimensional models. Macropinocytosis-associated genes are upregulated in tumor tissues and are correlated with worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified Zrt- and Irt-like protein 4 (ZIP4) as a downstream target of ACSS2, and knockdown of ZIP4 reversed ACSS2-induced macropinocytosis. ACSS2 upregulated ZIP4 through ETV4-mediated transcriptional activation. ZIP4 induces macropinocytosis through cyclic adenosine monophosphate response element-binding protein-activated syndecan 1 (SDC1) and dynamin 2 (DNM2). Meanwhile, ZIP4 drives muscle wasting and cachexia via glycogen synthase kinase-β (GSK3β)-mediated secretion of tumor necrosis factor superfamily member 10 (TRAIL or TNFSF10). ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models.
CONCLUSIONS: ACSS2-mediated metabolic reprogramming activates the ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through the GSK3β/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Zhou, Zhijun; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Ren, Yu; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Yang, Jingxuan; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Liu, Mingyang; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Shi, Xiuhui ; Université de Liège - ULiège > Département de pharmacie ; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Luo, Wenyi; Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Fung, Kar-Ming; Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Xu, Chao; Department of Biostatistics and Epidemiology, Hudson College of Public Health, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Bronze, Michael S; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Zhang, Yuqing; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: Yuqing-Zhang@ouhsc.edu
Houchen, Courtney W; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: courtney-houchen@ouhsc.edu
Li, Min ; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: Min-Li@ouhsc.edu
Language :
English
Title :
Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis and Muscle Wasting Through Metabolic Reprogramming in Pancreatic Cancer.
William and Ella Owens Medical Research Foundation NIH - National Institutes of Health
Funding text :
Funding This work was supported in part by National Institutes of Health National Cancer Institute grants R01 CA186338 , R01 CA203108 , R01 CA247234, and award P30 CA225520 , and by the William and Ella Owens Medical Research Foundation (Min Li).
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