Piecyk Marie, Triki Mouna, Laval Pierre-Alexandre, Dragic Helena, Cussonneau Laura, Fauvre Joelle, Duret Cédric, Aznar Nicolas, Renno Toufic, Manié Serge N, Chaveroux Cédric, Ferraro-Peyret Carole
Université Lyon, Cancer Research Centre of Lyon, INSERM 1052, CNRS 5286, F-69008 Lyon, France.
Hospices Civils de Lyon, Biopathology of Tumours, CPE, GHE Hospital, F-69500 Bron, France.
Metabolites. 2021 Mar 26;11(4):198. doi: 10.3390/metabo11040198.
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.
非小细胞肺癌（NSCLC）中的基因改变会刺激能量和生物量的产生，以促进肿瘤发展。然而，翻译过程的效率受到应激传感器的精细调节，而应激传感器本身又常常受营养物质可用性和化学毒性剂的控制。然而，治疗与葡萄糖可用性对细胞质量产生的相互作用仍未得到充分研究。在此，我们研究了培美曲塞（PEM）治疗（一种NSCLC一线治疗药物）对蛋白质合成的影响，具体取决于葡萄糖可用性的高低。当葡萄糖充足时，PEM治疗会显著抑制细胞质量和翻译。令人惊讶的是，在与PEM联合治疗时，低葡萄糖水平引起的蛋白质合成抑制会部分减轻。此外，PEM抵消了低葡萄糖可用性时产生的内质网应激（ERS）信号的升高，为该药物根据葡萄糖水平对翻译产生不同影响提供了分子解释。总体而言，这些数据表明ERS构成了微环境应激源之间的分子串扰，有助于翻译重编程和蛋白质稳态可塑性。
