H2O2 scavenging inhibits G1/S transition by increasing nuclear levels of p27KIP1

Ibañez, Irene L.; Policastro, L.; Tropper, Ivanna; Bracalente, Candelaria; Palmieri, Mónica A.; Rojas, Paulina S.; Molinari, Beatriz L.; Durán, Hebe

doi:10.1016/j.canlet.2011.02.026

Cited by 14 publications

(23 citation statements)

References 47 publications

(95 reference statements)

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“…This could explain the decrease in ROS levels observed in FBS starved cells in our melanoma model. Previously, we demonstrated decreased ROS levels in FBS starved squamous carcinoma cells [35]. We also observed that 0.1 µM of H 2 O 2 added to FBS starved A375 cells induced cell proliferation and it has been previously reported [26] that this dose results in a 10 nanomolar intracellular concentration of H 2 O 2 and directly stimulates cell proliferation.…”

Section: Discussionsupporting

confidence: 80%

“…In contrast, removal of endogenous H 2 O 2 by overexpression of catalase and glutathione peroxidase induces G0/G1 arrest [25] and decreases cell DNA synthesis [34]. A recent study of our laboratory showed increased levels of p27Kip1 in response to catalase treatment in a murine model of squamous cell carcinoma in vitro and in vivo [35]. However, the mechanisms involved in this cell cycle protein regulation by H 2 O 2 have not been fully understood.…”

Section: Introductionmentioning

confidence: 98%

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Phosphorylation and Subcellular Localization of p27Kip1 Regulated by Hydrogen Peroxide Modulation in Cancer Cells

et al. 2012

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The Cyclin-dependent kinase inhibitor 1B (p27Kip1) is a key protein in the decision between proliferation and cell cycle exit. Quiescent cells show nuclear p27Kip1, but this protein is exported to the cytoplasm in response to proliferating signals. We recently reported that catalase treatment increases the levels of p27Kip1 in vitro and in vivo in a murine model. In order to characterize and broaden these findings, we evaluated the regulation of p27Kip1 by hydrogen peroxide (H2O2) in human melanoma cells and melanocytes. We observed a high percentage of p27Kip1 positive nuclei in melanoma cells overexpressing or treated with exogenous catalase, while non-treated controls showed a cytoplasmic localization of p27Kip1. Then we studied the levels of p27Kip1 phosphorylated (p27p) at serine 10 (S10) and at threonine 198 (T198) because phosphorylation at these sites enables nuclear exportation of this protein, leading to accumulation and stabilization of p27pT198 in the cytoplasm. We demonstrated by western blot a decrease in p27pS10 and p27pT198 levels in response to H2O2 removal in melanoma cells, associated with nuclear p27Kip1. Melanocytes also exhibited nuclear p27Kip1 and lower levels of p27pS10 and p27pT198 than melanoma cells, which showed cytoplasmic p27Kip1. We also showed that the addition of H2O2 (0.1 µM) to melanoma cells arrested in G1 by serum starvation induces proliferation and increases the levels of p27pS10 and p27pT198 leading to cytoplasmic localization of p27Kip1. Nuclear localization and post-translational modifications of p27Kip1 were also demonstrated by catalase treatment of colorectal carcinoma and neuroblastoma cells, extending our findings to these other human cancer types. In conclusion, we showed in the present work that H2O2 scavenging prevents nuclear exportation of p27Kip1, allowing cell cycle arrest, suggesting that cancer cells take advantage of their intrinsic pro-oxidant state to favor cytoplasmic localization of p27Kip1.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 98%

Phosphorylation and Subcellular Localization of p27Kip1 Regulated by Hydrogen Peroxide Modulation in Cancer Cells

et al. 2012

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“…Tumorigenicity was completely inhibited in C10 and decreased in G10, consistent with the inhibition of proliferation and the antitumor effect of catalase [14, 58]. Even though A7 was tumorigenic, tumors were pigmented with increased expression of TYRP1.…”

Section: Discussionmentioning

confidence: 86%

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Reversion or promotion of malignancy by inducing melanogenesis or metastasis

et al. 2016

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Advanced melanoma is the most aggressive form of skin cancer. It is highly metastatic and dysfunctional in melanogenesis; two processes that are induced by H2O2. This work presents a melanoma cell model with low levels of H2O2 induced by catalase overexpression to study differentiation/dedifferentiation processes. Three clones (A7, C10 and G10) of human A375 amelanotic melanoma cells with quite distinct phenotypes were obtained. These clones faced H2O2 scavenging by two main strategies. One developed by clone G10 where ROS increased. This resulted in G10 migration and metastasis associated with the increased of cofilin-1 and CAP1. The other strategy was observed in clone A7 and C10, where ROS levels were maintained reversing malignant features. Particularly, C10 was not tumorigenic, while A7 reversed the amelanotic phenotype by increasing melanin content and melanocytic differentiation markers. These clones allowed the study of potential differentiation and migration markers and its association with ROS levels in vitro and in vivo, providing a new melanoma model with different degree of malignancy.

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“…Alterations in p53 functions can result in inaccurate and defective DNA repair, in formation of additional DNA mutations, in genome instability and finally in the enhancement of CSC survival and CSC aggressiveness. In carcinoma cells, ROS scavenging by proteins such as Ape1/Ref1 can reduce radiation sensitivity, and can also affect cell growth and the cell cycle [58][59][60]. It is currently not fully understood how ROS and ROS scavengers regulate CSC survival and cell cycle progression, but it The enhanced molecular signaling which allows these cells to survive after the tumor is exposed to ionizing radiation results in the generation of dormant or quiescent carcinoma cells.…”

Section: Ape1/ref1 As a Ros Scavenger In Cscsmentioning

confidence: 99%

Radiation resistance: Cancer stem cells (CSCs) and their enigmatic pro-survival signaling

Skvortsova

Debbage

Kumar

et al. 2015

Seminars in Cancer Biology

129

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H2O2 scavenging inhibits G1/S transition by increasing nuclear levels of p27KIP1

Cited by 14 publications

References 47 publications

Phosphorylation and Subcellular Localization of p27Kip1 Regulated by Hydrogen Peroxide Modulation in Cancer Cells

Phosphorylation and Subcellular Localization of p27Kip1 Regulated by Hydrogen Peroxide Modulation in Cancer Cells

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Reversion or promotion of malignancy by inducing melanogenesis or metastasis

Radiation resistance: Cancer stem cells (CSCs) and their enigmatic pro-survival signaling

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