Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy.
Department of Pharmacy and Biotechnology, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy.
Biochim Biophys Acta Gen Subj. 2022 Sep;1866(9):130185. doi: 10.1016/j.bbagen.2022.130185. Epub 2022 Jun 3.
Tamoxifen is a widely used estrogen receptor inhibitor, whose clinical success is limited by the development of acquired resistance. This compound was also found to inhibit mitochondrial function, causing increased glycolysis and lactate production. Lactate has been widely recognized as a signaling molecule, showing the potential of modifying gene expression. These metabolic effects of tamoxifen can by hypothesized to contribute in driving drug resistance.
To test this hypothesis, we used MCF7 cells together with a tamoxifen resistant cell line (MCF7-TAM). Experiments were aimed at verifying whether enhanced lactate exposure can affect the phenotype of MCF7 cells, conferring them features mirroring those observed in the tamoxifen resistant culture.
The obtained results suggested that enhanced lactate in MCF7 cells medium can increase the expression of tafazzin (TAZ) and telomerase complex (TERC, TERT) genes, reducing the cells' attitude to undergo senescence. In long term lactate-exposed cells, signs of EGFR activation, a pathway related to acquired tamoxifen resistance, was also observed.
The obtained results suggested lactate as a potential promoter of tamoxifen resistance. The off-target effects of this compound could play a role in hindering its therapeutic efficacy.
The features of acquired tamoxifen resistance have been widely characterized at the molecular level; in spite of their heterogeneity, poorly responsive cells were often found to display upregulated glycolysis. Our results suggest that this metabolic asset is not simply a result of neoplastic progression, but can play an active part in driving this process.
他莫昔芬是一种广泛应用的雌激素受体抑制剂，其临床疗效受到获得性耐药的限制。该化合物还被发现能抑制线粒体功能，导致糖酵解和乳酸生成增加。乳酸已被广泛认为是一种信号分子，具有修饰基因表达的潜力。他莫昔芬的这些代谢作用可假设有助于驱动耐药性的产生。
为了验证这一假说，我们使用 MCF7 细胞和他莫昔芬耐药细胞系（MCF7-TAM）进行实验。实验旨在验证增强的乳酸暴露是否会影响 MCF7 细胞的表型，使它们具有类似于在他莫昔芬耐药培养物中观察到的特征。
结果表明，增强 MCF7 细胞培养基中的乳酸可以增加 tafazzin（TAZ）和端粒酶复合物（TERC、TERT）基因的表达，降低细胞衰老的趋势。在长期暴露于乳酸的细胞中，还观察到 EGFR 激活的迹象，这是与获得性他莫昔芬耐药相关的途径。
结果表明，乳酸可能是他莫昔芬耐药的潜在促进剂。该化合物的脱靶效应可能在阻碍其治疗效果方面发挥作用。
获得性他莫昔芬耐药的特征已在分子水平上得到广泛描述；尽管它们具有异质性，但反应不良的细胞通常显示糖酵解上调。我们的结果表明，这种代谢特征不仅是肿瘤进展的结果，而且可以在推动这一过程中发挥积极作用。
