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Published on: July 21, 2018
Pemetrexed Hinders Translation Inhibition upon Low Glucose in Non-Small Cell Lung Cancer Cells
Marie Piecyk1,2, Mouna Triki1, Pierre-Alexandre Laval1
1Université Lyon, Cancer Research Centre of Lyon, INSERM 1052, CNRS 5286, F-69008 Lyon, France.
Abstract:
Genetic alterations in non-small cell lung cancers (NSCLC) stimulate the generation of energy and biomass to promote tumor development. However, the efficacy of the translation process is finely regulated by stress sensors, themselves often controlled by nutrient availability and chemotoxic agents. Yet, the crosstalk between therapeutic treatment and glucose availability on cell mass generation remains understudied. Herein, we investigated the impact of pemetrexed (PEM) treatment, a first-line agent for NSCLC, on protein synthesis, depending on high or low glucose availability. PEM treatment drastically repressed cell mass and translation when glucose was abundant. Surprisingly, inhibition of protein synthesis caused by low glucose levels was partially dampened upon co-treatment with PEM. Moreover, PEM counteracted the elevation of the endoplasmic reticulum stress (ERS) signal produced upon low glucose availability, providing a molecular explanation for the differential impact of the drug on translation according to glucose levels. Collectively, these data indicate that the ERS constitutes a molecular crosstalk between microenvironmental stressors, contributing to translation reprogramming and proteostasis plasticity.
Insights
Pemetrexed (PEM) impacts non-small cell lung cancer (NSCLC) cell mass differently based on glucose availability. PEM dampens protein synthesis inhibition under low glucose by counteracting endoplasmic reticulum stress (ERS).
Area of Science:
- Oncology
- Molecular Biology
- Cellular Stress Response
Background:
- Non-small cell lung cancer (NSCLC) growth relies on energy and biomass generation, regulated by translation.
- Nutrient availability and chemotoxic agents influence stress sensors that control translation.
- The interplay between chemotherapy and glucose levels on cancer cell mass is not well understood.
Purpose of the Study:
- To investigate the effect of pemetrexed (PEM) on protein synthesis in NSCLC cells under varying glucose conditions.
- To elucidate the molecular mechanisms underlying PEM's impact on translation based on glucose availability.
Main Methods:
- Culturing NSCLC cells under high and low glucose conditions.
- Treating cells with pemetrexed (PEM).
- Measuring cell mass, protein synthesis, and endoplasmic reticulum stress (ERS) markers.
Main Results:
- PEM significantly reduced cell mass and translation in high glucose conditions.
- Low glucose-induced inhibition of protein synthesis was partially alleviated by co-treatment with PEM.
- PEM counteracted the increase in ERS observed under low glucose conditions.
Conclusions:
- Glucose availability modulates the efficacy of PEM on protein synthesis in NSCLC.
- Endoplasmic reticulum stress (ERS) acts as a molecular link between nutrient status and drug response.
- ERS contributes to the adaptive reprogramming of translation and proteostasis during cancer therapy.
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