Relationships between LDH-A, lactate, and metastases in 4T1 breast tumors Journal Article


Authors: Rizwan, A.; Serganova, I.; Khanin, R.; Karabeber, H.; Ni, X.; Thakur, S.; Zakian, K. L.; Blasberg, R.; Koutcher, J. A.
Article Title: Relationships between LDH-A, lactate, and metastases in 4T1 breast tumors
Abstract: Purpose: To investigate the relationship between lactate dehydrogenase A (LDH-A) expression, lactate concentration, cell metabolism, and metastases in murine 4T1 breast tumors. Experimental Design: Inhibition of LDH-A expression and protein levels were achieved in a metastatic breast cancer cell line (4T1) using short hairpin RNA (shRNA) technology. The relationship between tumor LDH-A protein levels and lactate concentration (measured by magnetic resonance spectroscopic imaging, MRSI) and metastases was assessed. Results: LDH-A knockdown cells (KD9) showed a significant reduction in LDH-A protein and LDH activity, less acid production, decreased transwell migration and invasion, lower proliferation, reduced glucose consumption and glycolysis, and increase in oxygen consumption, reactive oxygen species (ROS), and cellular ATP levels, compared with control (NC) cells cultured in 25 mmol/L glucose. In vivo studies showed lower lactate levels in KD9, KD5, and KD317 tumors than in NCor 4T1 wild-type tumors (P < 0.01), and a linear relationship between tumor LDH-A protein expression and lactate concentration. Metastases were delayed and primary tumor growth rate decreased. Conclusions: We show for the first time that LDH-A knockdown inhibited the formation of metastases, and was accompanied by in vivo changes in tumor cell metabolism. Lactate MRSI can be used as a surrogate to monitor targeted inhibition of LDH-A in a preclinical setting and provides a noninvasive imaging strategy to monitor LDH-A-targeted therapy. This imaging strategy can be translated to the clinic to identify and monitor patients who are at high risk of developing metastatic disease. © 2013 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 19
Issue: 18
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2013-09-15
Start Page: 5158
End Page: 5169
Language: English
DOI: 10.1158/1078-0432.ccr-12-3300
PROVIDER: scopus
PUBMED: 23833310
PMCID: PMC3877680
DOI/URL:
Notes: --- - "Export Date: 1 November 2013" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Ronald G Blasberg
    242 Blasberg
  2. Sunitha Bai Thakur
    42 Thakur
  3. Kristen L Zakian
    74 Zakian
  4. Jason A Koutcher
    233 Koutcher
  5. Raya Khanin
    38 Khanin
  6. Asif Rizwan
    9 Rizwan
  7. Xiaohui Ni
    4 Ni