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Published on: December 26, 2016
Relationships between LDH-A, lactate, and metastases in 4T1 breast tumors
Asif Rizwan1, Inna Serganova, Raya Khanin
1Authors' Affiliations: Departments of Medical Physics, Neurology, Radiology, and Medicine, Bioinformatics Core, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center; and Department of Physiology and Biophysics, Weill Cornell Graduate School of Medical Sciences, New York, New York.
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 NC or 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.
Insights
Inhibiting lactate dehydrogenase A (LDH-A) in breast cancer cells reduced metastasis and altered tumor cell metabolism. Lactate magnetic resonance spectroscopic imaging (MRSI) can monitor this targeted therapy and identify high-risk patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lactate dehydrogenase A (LDH-A) plays a role in cancer cell metabolism.
- Understanding LDH-A's role in metastasis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the link between LDH-A expression, lactate levels, cell metabolism, and metastasis in 4T1 breast tumors.
- To assess the potential of lactate magnetic resonance spectroscopic imaging (MRSI) in monitoring LDH-A inhibition.
Main Methods:
- LDH-A expression was inhibited in 4T1 cells using short hairpin RNA (shRNA).
- Lactate concentration was measured using MRSI.
- In vitro and in vivo studies assessed cell migration, invasion, proliferation, and tumor growth.
Main Results:
- LDH-A knockdown significantly reduced LDH activity, acid production, migration, invasion, proliferation, and glucose consumption.
- Knockdown cells showed increased oxygen consumption, ROS, and ATP levels.
- In vivo, LDH-A knockdown tumors had lower lactate levels, delayed metastasis, and decreased primary tumor growth.
Conclusions:
- LDH-A inhibition suppresses metastasis and alters tumor cell metabolism.
- Lactate MRSI serves as a noninvasive imaging strategy to monitor LDH-A targeted therapy in preclinical models.
- This imaging approach can be translated to clinical settings for patient monitoring.
