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在营养受限的情况下，乳酸维持慢性髓性白血病细胞中的 BCR/Abl 表达和信号传导。

Lactate Maintains BCR/Abl Expression and Signaling in Chronic Myeloid Leukemia Cells Under Nutrient Restriction.

机构信息

Department of Experimental and Clinical Biomedical Sciences Mario Serio, Careggi Hospital, Universit degli Studi di FirenzeFlorenceItaly.

出版信息

Oncol Res. 2022 May 4;29(1):33-46. doi: 10.3727/096504022X16442289212164. Epub 2022 Feb 7.

DOI:10.3727/096504022X16442289212164
PMID:35131002
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9110649/
Abstract

This study was directed to deepen the effects of nutrient shortage on BCR/Abl expression and signaling in chronic myeloid leukemia (CML) cells. The backbone of the study was cell culture in medium lacking glucose, the consumption of which we had previously shown to drive BCR/Abl suppression, and glutamine, the other main nutrient besides glucose. In this context, we focused on the role of lactate, the main by-product of glucose metabolism under conditions of rapid cell growth, in particular as a modulator of the maintenance of CML stem/progenitor cell potential, a crucial determinant of disease course and relapse of disease. The results obtained indicated that lactate is a powerful surrogate of glucose to prevent the suppression of BCR/Abl signaling and is therefore capable to maintain BCR/Abl-dependent CML stem/progenitor cell potential. A number of metabolism-related functional and phenotypical features of CML cells were also determined. Among these, we focused on the effect of lactate on oxygen consumption rate, the dependence of this effect on the cell surface lactate carrier MCT-1, and the relationship of the lactate effect to pyruvate and to the activity of mitochondrial pyruvate carrier.

摘要

本研究旨在深入探讨营养缺乏对慢性髓系白血病 (CML) 细胞中 BCR/Abl 表达和信号的影响。研究的重点是在缺乏葡萄糖和谷氨酰胺的培养基中进行细胞培养，我们之前的研究表明，葡萄糖的消耗会导致 BCR/Abl 抑制，而谷氨酰胺是除葡萄糖之外的另一种主要营养物质。在这种情况下，我们专注于乳酸的作用，乳酸是快速细胞生长条件下葡萄糖代谢的主要副产物，特别是作为 CML 干细胞/祖细胞潜能维持的调节剂，这是疾病过程和疾病复发的关键决定因素。研究结果表明，乳酸是一种强大的葡萄糖替代物，可以防止 BCR/Abl 信号的抑制，因此能够维持 BCR/Abl 依赖性 CML 干细胞/祖细胞潜能。还确定了 CML 细胞的一些与代谢相关的功能和表型特征。在这些特征中，我们重点研究了乳酸对耗氧量的影响，这种影响对细胞表面乳酸载体 MCT-1 的依赖性，以及乳酸效应与丙酮酸和线粒体丙酮酸载体活性的关系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/fa143921b024/OR-29-33-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/fed59bbe3767/OR-29-33-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/fa143921b024/OR-29-33-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/fed59bbe3767/OR-29-33-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/fbf922fa3681/OR-29-33-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/fb126cc08564/OR-29-33-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/2e5772d4ba85/OR-29-33-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/ef4d2229e517/OR-29-33-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/0e606c8a3c35/OR-29-33-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a358/9110649/fa143921b024/OR-29-33-g007.jpg

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Metabolic Interactions in the Tumor Microenvironment.
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Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: Interplay between hematologic and solid neoplastic clones and their microenvironments.乳酸脱氢酶（LDH）升高可能是癌症免疫抑制的一个标志物：血液学和实体肿瘤克隆及其微环境之间的相互作用。
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