Related Experiment Video
Updated: Mar 31, 2026
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards
Balkrishna Chaube1, Parmanand Malvi1, Shivendra Vikram Singh1
1National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
Abstract:
Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma.
Insights
Metformin inhibition of complex I in melanoma paradoxically increases tumor growth by raising lactate. Blocking lactate production or lactate dehydrogenase halts melanoma progression, revealing a synthetic lethality strategy.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer research
Background:
- Melanoma exhibits metabolic flexibility, utilizing either oxidative phosphorylation (OXPHOS) or glycolysis for energy.
- Metabolic heterogeneity and resistance complicate melanoma treatment.
- Understanding metabolic dependencies is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the roles of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression.
- To explore the therapeutic potential of targeting these metabolic pathways.
Main Methods:
- Inhibition of complex I using metformin in a mouse melanoma model.
- Inhibition of lactate dehydrogenase (LDH) or lactate generation.
- Assessment of melanoma cell proliferation, tumor growth, extracellular acidification, and apoptosis in vitro and in vivo.
Main Results:
- Metformin inhibition of complex I promoted melanoma growth in mice by increasing lactate and VEGF.
- Metformin induced in vitro growth arrest due to enhanced extracellular acidification from increased glycolysis.
- Inhibition of LDH or lactate generation led to growth arrest both in vitro and in vivo.
- Combined inhibition of LDH and complex I resulted in ATP depletion and apoptosis, indicating synthetic lethality.
Conclusions:
- Lactate dehydrogenase (LDH) and complex I play distinct roles in regulating melanoma glycolysis and proliferation.
- Targeting both LDH and complex I simultaneously can induce synthetic lethality in melanoma.
- This study suggests a novel therapeutic strategy for treating melanoma by exploiting its metabolic vulnerabilities.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...