Voulgaridou Georgia-Persephoni, Kiziridou Magdalini, Mantso Theodora, Chlichlia Katerina, Galanis Alex, Koukourakis Michael I, Franco Rodrigo, Panayiotidis Mihalis I, Pappa Aglaia
Departments of Molecular Biology & Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Departments of Molecular Biology & Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece; Heriot-Watt University, School of Life Sciences, Edinburgh, EH14 4AS Scotland, UK.
Int J Biochem Cell Biol. 2016 Aug;77(Pt A):120-128. doi: 10.1016/j.biocel.2016.06.004. Epub 2016 Jun 6.
Aldehyde dehydrogenases participate in a variety of cellular homeostatic mechanisms like metabolism, proliferation, differentiation, apoptosis, whereas recently, they have been implicated in normal and cancer cell stemness. We explored roles for ALDH3A1 in conferring resistance to chemotherapeutics/radiation/oxidative stress and whether ectopic overexpression of ALDH3A1 could lead to alterations of gene expression profile associated with cancer stem cell-like phenotype. MCF-7 cells were stably transfected either with an empty vector (mock) or human aldehyde dehydrogenase 3A1 cDNA. The expression of aldehyde dehydrogenase 3A1 in MCF-7 cells was associated with altered cell proliferation rate and enhanced cell resistance against various chemotherapeutic drugs (4-hydroxyperoxycyclophosphamide, doxorubicin, etoposide, and 5-fluorouracil). Aldehyde dehydrogenase 3A1 expression also led to increased tolerance of MCF-7 cells to gamma radiation and hydrogen peroxide-induced stress. Furthermore, aldehyde dehydrogenase 3A1-expressing MCF-7 cells exhibited gene up-regulation of cyclins A, B1, B2, and down-regulation of cyclin D1 as well as transcription factors p21, CXR4, Notch1, SOX2, SOX4, OCT4, and JAG1. When compared to mock cells, no changes were observed in mRNA levels of ABCA2 and ABCB1 protein pumps with only a minor decrease of the ABCG2 pump in the aldehyde dehydrogenase 3A1-expressing cells. Also, the adhesion molecules EpCAM and CD49F were also found to be up-regulated in aldehyde dehydrogenase 3A1expressing cells. Taken together, ALDH3A1 confers a multi-modality resistance phenotype in MCF-7 cells associated with slower growth rate, increased clonogenic capacity, and altered gene expression profile, underlining its significance in cell homeostasis.
醛脱氢酶参与多种细胞稳态机制，如代谢、增殖、分化、凋亡，而最近，它们被认为与正常细胞和癌细胞的干性有关。我们探讨了醛脱氢酶3A1（ALDH3A1）在赋予对化疗药物/辐射/氧化应激抗性中的作用，以及ALDH3A1的异位过表达是否会导致与癌症干细胞样表型相关的基因表达谱改变。MCF-7细胞用空载体（mock）或人醛脱氢酶3A1 cDNA进行稳定转染。醛脱氢酶3A1在MCF-7细胞中的表达与细胞增殖速率改变以及对多种化疗药物（4-羟基过氧环磷酰胺、阿霉素、依托泊苷和5-氟尿嘧啶）的抗性增强有关。醛脱氢酶3A1的表达还导致MCF-7细胞对γ辐射和过氧化氢诱导的应激耐受性增加。此外，表达醛脱氢酶3A1的MCF-7细胞表现出细胞周期蛋白A、B1、B2的基因上调以及细胞周期蛋白D1以及转录因子p21、CXR4、Notch1、SOX2、SOX4、OCT4和JAG1的下调。与mock细胞相比，ABCA2和ABCB1蛋白泵的mRNA水平没有变化，仅在表达醛脱氢酶3A1的细胞中ABCG2泵略有下降。此外，在表达醛脱氢酶3A1的细胞中还发现粘附分子EpCAM和CD49F上调。综上所述，ALDH3A1在MCF-7细胞中赋予多模态抗性表型，与生长速率减慢、克隆形成能力增加和基因表达谱改变有关，突显了其在细胞稳态中的重要性。
