Graduate Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201, USA.
Graduate Program in Molecular Medicine, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201, USA.
Cells. 2023 Apr 27;12(9):1266. doi: 10.3390/cells12091266.
Levels of hydrogen peroxide are highly elevated in the breast tumor microenvironment compared to normal tissue. Production of hydrogen peroxide is implicated in the mechanism of action of many anticancer therapies. Several lines of evidence suggest hydrogen peroxide mediates breast carcinogenesis and metastasis, though the molecular mechanism remains poorly understood. This study elucidates the effects of exposure to elevated hydrogen peroxide on non-tumorigenic MCF10A mammary epithelial cells, tumorigenic MCF7 cells, and metastatic MDA-MB-231 breast cancer cells. Hydrogen peroxide treatment resulted in a dose- and time-dependent induction of two α-tubulin post-translational modifications-de-tyrosination and acetylation-both of which are markers of poor patient prognosis in breast cancer. Hydrogen peroxide induced the formation of tubulin-based microtentacles in MCF10A and MDA-MB-231 cells, which were enriched in detyrosinated and acetylated α-tubulin. However, the hydrogen peroxide-induced microtentacles did not functionally promote metastatic phenotypes of cellular reattachment and homotypic cell clustering. These data establish for the first time that microtentacle formation can be separated from the functions to promote reattachment and clustering, which indicates that there are functional steps that remain to be identified. Moreover, signals in the primary tumor microenvironment may modulate α-tubulin post-translational modifications and induce microtentacles; however, the functional consequences appear to be context-dependent.
过氧化氢的水平在乳腺癌肿瘤微环境中比正常组织高得多。过氧化氢的产生与许多抗癌疗法的作用机制有关。有几条证据表明过氧化氢介导乳腺癌的发生和转移，尽管其分子机制仍不清楚。本研究阐明了暴露于高浓度过氧化氢对非致瘤性 MCF10A 乳腺上皮细胞、致瘤性 MCF7 细胞和转移性 MDA-MB-231 乳腺癌细胞的影响。过氧化氢处理导致两种α-微管蛋白翻译后修饰——去酪氨酸化和乙酰化的剂量和时间依赖性诱导，这两种修饰都是乳腺癌患者预后不良的标志物。过氧化氢诱导 MCF10A 和 MDA-MB-231 细胞中基于微管蛋白的微绒毛的形成，这些微绒毛富含去酪氨酸化和乙酰化的α-微管蛋白。然而，过氧化氢诱导的微绒毛在功能上并没有促进细胞再附着和同型细胞聚集的转移表型。这些数据首次建立了微绒毛的形成可以与促进再附着和聚集的功能分离，这表明仍然需要确定功能步骤。此外，原发肿瘤微环境中的信号可能调节α-微管蛋白翻译后修饰并诱导微绒毛；然而，功能后果似乎取决于上下文。
