Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1 β

被引:51
作者
Zhao, Wei [1 ]
Chang, Cunjie [1 ]
Cui, Yangyan [1 ]
Zhao, Xiaozhi [3 ,5 ]
Yang, Jun [4 ]
Shen, Lan [1 ]
Zhou, Ji [6 ]
Hou, Zhibo [7 ]
Zhang, Zhen [2 ]
Ye, Changxiao [3 ]
Hasenmayer, Donald [8 ]
Perkins, Robert [8 ]
Huang, Xiaojing [1 ]
Yao, Xin [6 ]
Yu, Like [7 ]
Huang, Ruimin [9 ]
Zhang, Dianzheng [8 ]
Guo, Hongqian [3 ,5 ]
Yan, Jun [1 ,2 ]
机构
[1] Nanjing Univ, MOE Key Lab Model Anim Dis Study, Model Anim Res Ctr, Nanjing Biomed Res Inst, Nanjing 210008, Jiangsu, Peoples R China
[2] Wenzhou Med Coll, Zhejiang Prov Key Lab Technol & Applicat Model Or, Sch Life Sci, Wenzhou 325035, Zhejiang, Peoples R China
[3] Nanjing Univ, Sch Med, Nanjing Drum Tower Hosp, Dept Urol, Nanjing 210008, Jiangsu, Peoples R China
[4] Nanjing Univ, Sch Med, Nanjing Drum Tower Hosp, Dept Pathol, Nanjing 210008, Jiangsu, Peoples R China
[5] Nanjing Urol Res Ctr, Nanjing 210008, Jiangsu, Peoples R China
[6] Nanjing Med Univ, Affiliated Hosp 1, Dept Resp Med, Nanjing 210029, Jiangsu, Peoples R China
[7] Nanjing Chest Hosp, Dept Resp Med 1, Nanjing 210029, Jiangsu, Peoples R China
[8] Philadelphia Coll Osteopath Med, Philadelphia, PA 19131 USA
[9] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA
关键词
Cancer; Cell Proliferation; Glycolysis; Transcription Coactivators; Tumor Metabolism; HIF1; SRC-3; Urinary Bladder Cancer; TRANSCRIPTIONAL COACTIVATOR; LACTATE-DEHYDROGENASE; UROTHELIAL CARCINOMA; SRC-3; COACTIVATOR; GENE-EXPRESSION; AIB1; PROLIFERATION; ACTIVATION; BREAST; OVEREXPRESSION;
D O I
10.1074/jbc.M113.535989
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Steroid receptor coactivator-3 (SRC-3) is frequently overexpressed in human urinary bladder cancer. Results: SRC-3 promotes urinary bladder cancer (UBC) cells proliferation through coactivating HIF1 and up-regulating the expression of genes involved in the glycolytic pathway. Conclusion: SRC-3 plays an important role in UBC development through enhancing glycolysis. Significance: Targeting SRC-3 or enzymes in glycolytic pathway could be an attractive approach in UBC therapy. Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as Warburg effect, to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1 (HIF1), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1 to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.
引用
收藏
页码:11219 / 11229
页数:11
相关论文
共 46 条
  • [1] AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer
    Anzick, SL
    Kononen, J
    Walker, RL
    Azorsa, DO
    Tanner, MM
    Guan, XY
    Sauter, G
    Kallioniemi, OP
    Trent, JM
    Meltzer, PS
    [J]. SCIENCE, 1997, 277 (5328) : 965 - 968
  • [2] The health economics of bladder cancer - A comprehensive review of the published literature
    Botteman, MF
    Pashos, CL
    Redaelli, A
    Laskin, B
    Hauser, R
    [J]. PHARMACOECONOMICS, 2003, 21 (18) : 1315 - 1330
  • [3] Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model
    Brader, Peter
    Riedl, Christopher Cesare
    Woo, Yanghee
    Ponomarev, Vladimir
    ZanzoniCO, Pat
    Wen, Bixiu
    Cai, Shangde
    Hricak, Hedvig
    Fong, Yuman
    Blasberg, Ronald
    Serganova, Inna
    [J]. MOLECULAR CANCER THERAPEUTICS, 2007, 6 (11) : 2900 - 2908
  • [4] Molecular pathways of urothelial development and bladder tumorigenesis
    Castillo-Martin, Mireia
    Domingo-Domenech, Josep
    Karni-Schmidt, Orit
    Matos, Tulio
    Cordon-Cardo, Carlos
    [J]. UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS, 2010, 28 (04) : 401 - 408
  • [5] Mitochondria-Targeted Drugs Synergize with 2-Deoxyglucose to Trigger Breast Cancer Cell Death
    Cheng, Gang
    Zielonka, Jacek
    Dranka, Brian P.
    McAllister, Donna
    Mackinnon, A. Craig, Jr.
    Joseph, Joy
    Kalyanaraman, Balaraman
    [J]. CANCER RESEARCH, 2012, 72 (10) : 2634 - 2644
  • [6] Structural basis for Hif-1α/CBP recognition in the cellular hypoxic response
    Dames, SA
    Martinez-Yamout, M
    De Guzman, RN
    Dyson, HJ
    Wright, PE
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (08) : 5271 - 5276
  • [7] Protein kinase C ζ transactivates hypoxia-inducible factor α by promoting its association with p300 in renal cancer
    Datta, K
    Li, JP
    Bhattacharya, R
    Gasparian, L
    Wang, EF
    Mukhopadhyay, D
    [J]. CANCER RESEARCH, 2004, 64 (02) : 456 - 462
  • [8] Hypoxia, HIF1 and glucose metabolism in the solid tumour
    Denko, Nicholas C.
    [J]. NATURE REVIEWS CANCER, 2008, 8 (09) : 705 - 713
  • [9] Gene expression in the urinary bladder:: A common carcinoma in situ gene expression signature exists disregarding histopathological classification
    Dyrskjot, L
    Kruhoffer, M
    Thykjaer, T
    Marcussen, N
    Jensen, JL
    Moller, K
    Orntoft, TF
    [J]. CANCER RESEARCH, 2004, 64 (11) : 4040 - 4048
  • [10] Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target
    Gerlinger, Marco
    Santos, Claudio R.
    Spencer-Dene, Bradley
    Martinez, Pierre
    Endesfelder, David
    Burrell, Rebecca A.
    Vetter, Marcus
    Jiang, Ming
    Saunders, Rebecca E.
    Kelly, Gavin
    Dykema, Karl
    Rioux-Leclercq, Nathalie
    Stamp, Gordon
    Patard, Jean Jacques
    Larkin, James
    Howell, Michael
    Swanton, Charles
    [J]. JOURNAL OF PATHOLOGY, 2012, 227 (02) : 146 - 156