Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms

Parasassi, Tiziana; Brunelli, Roberto; Bracci-Laudiero, Luisa; Greco, Giulia; Gustafsson, Anna; Krasnowska, Ewa K.; Lundeberg, Joakim; Lundeberg, Thomas; Pittaluga, Eugenia; Romano, Maria-Concetta; Serafino, Annalucia

doi:10.1038/sj.cdd.4401663

Cited by 52 publications

(60 citation statements)

References 44 publications

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“…This was consistent with the previous data, as SAOS-2 cells can be differentiated by a master regulator of osteoblast differentiation (RUNX2/CBFA1) along with reintroduction of pRB (Thomas et al 2001) or KDM5A knockdown (Benevolenskaya et al 2005). As a control for the C33A cell line, we used treatment with the antioxidant N-acetyl L-cysteine (NAC), which is known to induce keratinocyte differentiation in colon and ovarian cancer cell lines (Parasassi et al 2005).…”

Section: Growth Of Human Rb-negative Cell Lines Is Responsive To Kdm5supporting

confidence: 74%

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

et al. 2015

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The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell typespecific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.

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Section: Growth Of Human Rb-negative Cell Lines Is Responsive To Kdm5supporting

confidence: 74%

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

et al. 2015

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“…However, recent work from our laboratory and those of the others established other important functions for NAC which could be the basis for its death inhibitory property [12,13]. Here we demonstrate that the basis for cell death inhibitory function of NAC could be its capacity to induce NFκB, and modulate important differentiation and activation genes in DPSCs.…”

Section: Discussionsupporting

confidence: 53%

“…[12,13]. In contrast, significant increases in the cell proliferation and cell numbers was seen when NAC was added to untreated and HEMA treated cells when compared to HEMA alone treated cells.…”

Section: Discussionmentioning

confidence: 85%

“…NAC is shown to be the precursor of glutathiones (GSH) with a significant antioxidant effect. Although previously published reports on the function of NAC have largely been concentrated on its anti-oxidant effect, recent reports have underscored the significance of this compound in inhibition of proliferation and induction of differentiation [12][13][14]. NAC has also been regarded as an anti-inflammatory compound [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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N-acetylcysteine protects dental pulp stromal cells from HEMA-induced apoptosis by inducing differentiation of the cells

Paranjpe

Cacalano

Hume

et al. 2007

Free Radical Biology and Medicine

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Resin based materials are now widely used in dental restorations. While the use of these materials is aesthetically appealing in patients, they carry the risk of local and systemic adverse effects. The potential risks are direct damage to the cells and induction of immune-based hypersensitivity reactions. Dental Pulp Stromal Cells (DPSCs) and oral keratinocytes are the major cell types which may come in contact with dental resins such as 2-hydroxyethyl methacrylate (HEMA) after dental restorations. Here we show that N-acetyl cysteine (NAC) inhibits HEMA induced apoptotic cell death and restores the function of DPSCs and oral epithelial cells. NAC inhibits HEMA mediated toxicity through induction of differentiation in DPSCs since the genes for dentin sialoprotein (DSP), Osteopontin (OPN), Osteocalcin (OCN), and Alkaline Phosphatase (ALP) which are induced during differentiation are also induced by NAC. Unlike NAC, Vitamin E and C which known anti-oxidant compounds failed to prevent either HEMA mediated cell death or decrease in VEGF secretion by human DPSCs. More importantly, when added either alone or in combination with HEMA Vitamin E and Vitamin C did not increase the gene expression for OPN, and in addition Vitamin E inhibited the protective effect of NAC on DPSCs. NAC inhibited HEMA mediated decrease in NFκB activity thus, providing survival mechanism for the cells. Overall, the studies reported in this paper indicated that undifferentiated DPSCs have exquisite sensitivity to HEMA induced cell death, and their differentiation by NAC resulted in an increased NFκB activity which might have provided the basis for their increased protection from HEMA mediated functional loss and cell death.

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“…In Atm-/-mice, NAC reduces ROS level in HSC and normalizes their size, cell cycling, apoptosis level (Tothova et al, 2007) and improves long-term self-renewal capacity (Ito et al, 2006). NAC also facilitates the differentiation of various cell types such as mouse calvarial cells (Jun et al, 2008), rat and human dental pulp stromal cells (Paranjpe et al, 2007), human primary keratinocytes and human colony and ovary carcinoma cells (Parasassi et al, 2005), and mouse embryonic stem cells (Qian et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

N-acetylcysteine protects induced pluripotent stem cells from in vitro stress: impact on differentiation outcome

Berniakovich¹,

Laricchia-Robbio²,

Belmonte

2012

Int. J. Dev. Biol.

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Induced pluripotent stem cells (iPSCs) have the ability to differentiate towards various cell types of the adult organism and are a potential source of transplantable material in regenerative medicine. The entire process of conversion of iPSCs into terminally differentiated cells takes place in vitro and requires long periods of time. During in vitro culture, cells are exposed to environmental factors, which are capable of decreasing cellular performance and viability. Oxidative stress is the major underlying mechanism of such negative impact of in vitro environmental factors. We aimed to study the alteration of cellular properties during in vitro hematopoietic differentiation of human iPSCs and the ability of N-acetylcysteine (NAC), a potent free radical scavenger, to prevent such alterations. IPSCs were differentiated towards hematopoietic cells in the presence of 1 mM NAC. Intracellular reactive oxygen species (ROS), nitric oxide (NO), senescence, apoptosis and mitochondrial membrane potential (MMP) were evaluated at 1 and 3 weeks of differentiation. In the course of hematopoietic differentiation of iPSCs, cells progressively accumulated intracellular ROS and NO, increased the levels of apoptosis and senescence, and showed a decrease in mitochondrial functionality. NAC supplementation reversed all these phenomena. NAC administration also improved hematopoietic differentiation of iPSCs in terms of production of CD34, CD45 and CD43 positive cells. In conclusion, when supplemented during hematopoietic differentiation of iPSCs, NAC decreased oxidative stress, rescued the decline in cellular properties induced by long-term in vitro culture and promoted hematopoietic differentiation of iPSCs.

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Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms

Cited by 52 publications

References 44 publications

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

N-acetylcysteine protects dental pulp stromal cells from HEMA-induced apoptosis by inducing differentiation of the cells

N-acetylcysteine protects induced pluripotent stem cells from in vitro stress: impact on differentiation outcome

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