Inhibition of nuclear Nox4 activity by plumbagin: effect on proliferative capacity in human amniotic stem cells.
Human amniotic fluid stem cells (AFSC) with multilineage differentiation potential are novel source for cell therapy. However, in vitro expansion leads to senescence affecting differentiation and proliferative capacities. Reactive oxygen species (ROS) have been involved in the regulation of stem cell pluripotency, proliferation, and differentiation. Redox-regulated signal transduction is coordinated by spatially controlled production of ROS within subcellular compartments. NAD(P)H oxidase family, in particular Nox4, has been known to produce ROS in the nucleus; however, the mechanisms and the meaning of this function remain largely unknown. In the present study, we show that Nox4 nuclear expression (nNox4) increases during culture passages up to cell cycle arrest and the serum starvation causes the same effect. With the decrease of Nox4 activity, obtained with plumbagin, a decline of nuclear ROS production and of DNA damage occurs. Moreover, plumbagin exposure reduces the binding between nNox4 and nucleoskeleton components, as Matrin 3. The same effect was observed also for the binding with phospho-ERK, although nuclear ERK and P-ERK are unchanged. Taken together, we suggest that nNox4 regulation may have important pathophysiologic effects in stem cell proliferation through modulation of nuclear signaling and DNA damage.
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
Marianna
M
Guida
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
Tullia
T
Maraldi
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
Elisa
E
Resca
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
Francesca
F
Beretti
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
Manuela
M
Zavatti
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
Laura
L
Bertoni
Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Viale Risorgimento 80, 42100 Reggio Emilia, Italy.
Giovanni B
GB
La Sala
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
Anto
A
De Pol
D000328:Adult; D000653:Amniotic Fluid / Q000166:cytology*; D002467:Cell Nucleus / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D044967:Serum / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C014758:plumbagin