Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer
Yaping Shao
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, China
Y.S., G.Y. and S.R. contributed equally to this work
Search for more papers by this authorGuozhu Ye
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, China
Y.S., G.Y. and S.R. contributed equally to this work
Search for more papers by this authorShancheng Ren
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Y.S., G.Y. and S.R. contributed equally to this work
Search for more papers by this authorHai-Long Piao
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorXinjie Zhao
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorXin Lu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorFubo Wang
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Search for more papers by this authorWang Ma
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Jianshedong Road, Zhengzhou, China
Search for more papers by this authorJia Li
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, China
Search for more papers by this authorPeiyuan Yin
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorTian Xia
Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorChuanliang Xu
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Search for more papers by this authorJane J. Yu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Jianshedong Road, Zhengzhou, China
Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267, USA
Search for more papers by this authorCorresponding Author
Yinghao Sun
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Correspondence to: Guowang Xu, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China, Tel.: 86-411-84379559, Fax: 86-411-84379559, E-mail: [email protected]; or Yinghao Sun, Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China, Tel.: 86-021-65566429, Fax: 86-021-65566429, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Guowang Xu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Correspondence to: Guowang Xu, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China, Tel.: 86-411-84379559, Fax: 86-411-84379559, E-mail: [email protected]; or Yinghao Sun, Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China, Tel.: 86-021-65566429, Fax: 86-021-65566429, E-mail: [email protected]Search for more papers by this authorYaping Shao
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, China
Y.S., G.Y. and S.R. contributed equally to this work
Search for more papers by this authorGuozhu Ye
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, China
Y.S., G.Y. and S.R. contributed equally to this work
Search for more papers by this authorShancheng Ren
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Y.S., G.Y. and S.R. contributed equally to this work
Search for more papers by this authorHai-Long Piao
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorXinjie Zhao
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorXin Lu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorFubo Wang
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Search for more papers by this authorWang Ma
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Jianshedong Road, Zhengzhou, China
Search for more papers by this authorJia Li
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, China
Search for more papers by this authorPeiyuan Yin
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorTian Xia
Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Search for more papers by this authorChuanliang Xu
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Search for more papers by this authorJane J. Yu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Jianshedong Road, Zhengzhou, China
Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267, USA
Search for more papers by this authorCorresponding Author
Yinghao Sun
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
Correspondence to: Guowang Xu, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China, Tel.: 86-411-84379559, Fax: 86-411-84379559, E-mail: [email protected]; or Yinghao Sun, Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China, Tel.: 86-021-65566429, Fax: 86-021-65566429, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Guowang Xu
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China
Correspondence to: Guowang Xu, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China, Tel.: 86-411-84379559, Fax: 86-411-84379559, E-mail: [email protected]; or Yinghao Sun, Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China, Tel.: 86-021-65566429, Fax: 86-021-65566429, E-mail: [email protected]Search for more papers by this authorGrant sponsor: The National Key Research and Development Program of China; Grant number: 2017YFC0906900; Grant sponsor: National Basic Research Program of China; Grant numbers: 2012CB518303 and 2012CB518306; Grant sponsor: The Key Program; Grant number: 21435006; Grant sponsor: The National Natural Science Foundation of China; Grant numbers: (general projects) 81430058, 81101946 and 81472397
Abstract
Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography–mass spectrometry (GC–MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.
Abstract
What's new?
Although many studies have reported accelerated tricarboxylic acid (TCA) cycle in prostate cancer (PCa) cells, the underlying metabolic reprogramming and molecular mechanisms remain elusive. Here, the authors systematically investigated the molecular changes in TCA cycle through metabolomics and transcriptomics analysis of matched normal and PCa tissues. Fumarate and malate were found to be highly correlated with tumor progression and expression of related genes. Potential anaplerotic routes from pyruvate, glutamine catabolism, and BCAA degradation contributed to replenishing metabolites for TCA cycle. These observations provide new molecular insight into PCa carcinogenesis and may facilitate the development of new and effective therapeutic strategies.
Supporting Information
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