Aldehyde dehydrogenase 3A1 promotes multi-modality resistance and alters gene expression profile in human breast adenocarcinoma MCF-7 cells.
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.
Departments of Molecular Biology & Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Georgia-Persephoni
GP
Voulgaridou
Departments of Molecular Biology & Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Magdalini
M
Kiziridou
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.
Theodora
T
Mantso
Departments of Molecular Biology & Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Katerina
K
Chlichlia
Departments of Molecular Biology & Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Alex
A
Galanis
Division of Radiotherapy/Oncology, Radiopathology & Radiobiology Unit, Department of Medicine, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Michael I
MI
Koukourakis
Department of Redox Biology Center and School of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
Rodrigo
R
Franco
Heriot-Watt University, School of Life Sciences, Edinburgh, EH14 4AS Scotland, UK.
Mihalis I
MI
Panayiotidis
Departments of Molecular Biology & Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupolis 68100, Greece. Electronic address: apappa@mbg.duth.gr.
Aglaia
A
Pappa
D000230:Adenocarcinoma / Q000473:pathology*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D061986:MCF-7 Cells; D011836:Radiation Tolerance / Q000235:genetics
D006861:Hydrogen Peroxide; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase
ALDH; ALDH3A1; Breast cancer; CD49F; Cancer stem cells; Chemoresistance; EpCAM; MCF-7; Oxidative stress