A dual role of p21waf1/cip1 gene in apoptosis of HEp-2 treated with cisplatin or methotrexate

Pavelić, Sandra Kraljević; Čačev, Tamara; Kralj, Marijeta

doi:10.1038/cgt.2008.28

Cited by 22 publications

(19 citation statements)

References 38 publications

(59 reference statements)

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“…Later, the implication of p21 in apoptosis was revealed. Previous reports indicate the contradictive effects of p21 on apoptosis: anti- and pro-apoptotic activities (24, 32), which might be influenced by several factors including the nature of the apoptotic stimuli (33), subcellular localization (34), and the extent of DNA damage (35). It was reported that human prostate cancer cell line LNCaP is resistant to docetaxel-induced apoptosis because docetaxel treatment results in the up-regulation of p53 and p21 proteins mediated by p38 phosphorylation, and that knockdown of p21 sensitizes LNCaP cells to docetaxel treatment (36).…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 regulates p21 stability in human prostate cancer cells

et al. 2012

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Galectin-3 (Gal-3) is a multifunctional protein involved in cancer through regulation of cell adhesion, cell growth, apoptosis, and metastasis, while p21 (Cip1/WAF1) is a negative regulator of the cell cycle, involved in apoptosis, transcription, DNA repair and metastasis. The results presented here demonstrate for the first time that the level of Gal-3 protein is associated with the level of p21 protein expression in human prostate cancer cells and the effects of Gal-3 on cell growth and apoptosis were reversed by modulating p21 expression level. Furthermore, Gal-3 regulates p21 expression at the post-translational level by stabilizing p21 protein via the carbohydrate-recognition domain (CRD). This is the first report suggesting a molecular function not yet described for Gal-3 as the regulator of p21 protein stability. This study provides a unique insight into the relationship of these two molecules during prostate cancer progression, and may provide a novel therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Galectin-3 regulates p21 stability in human prostate cancer cells

et al. 2012

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“…This conclusion is in line with the observation that p21 attenuates apoptotic signals in methotrexatetreated cells. 69 Of note, both methotrexate and FDH work in the same direction with regard to folate metabolism, inhibiting folate-dependent biosynthetic reactions. The activation of p21, however, is not sufficient to rescue cells from FDH-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Activation of p21-Dependent G1/G2 Arrest in the Absence of DNA Damage as an Antiapoptotic Response to Metabolic Stress

et al. 2011

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The folate enzyme, FDH (10-formyltetrahydrofolate dehydrogenase, ALDH1L1), a metabolic regulator of proliferation, activates p53-dependent G1 arrest and apoptosis in A549 cells. In the present study, we have demonstrated that FDH-induced apoptosis is abrogated upon siRNA knockdown of the p53 downstream target PUMA. Conversely, siRNA knockdown of p21 eliminated FDH-dependent G1 arrest and resulted in an early apoptosis onset. The acceleration of FDH-dependent apoptosis was even more profound in another cell line, HCT116, in which the p21 gene was silenced through homologous recombination (p21 -/-cells). In contrast to A549 cells, FDH caused G2 instead of G1 arrest in HCT116 p21 +/+ cells; such an arrest was not seen in p21-deficient (HCT116 p21 -/-) cells. In agreement with the cell cycle regulatory function of p21, its strong accumulation in nuclei was seen upon FDH expression. Interestingly, our study did not reveal DNA damage upon FDH elevation in either cell line, as judged by comet assay and the evaluation of histone H2AX phosphorylation. In both A549 and HCT116 cell lines, FDH induced a strong decrease in the intracellular ATP pool (2-fold and 30-fold, respectively), an indication of a decrease in de novo purine biosynthesis as we previously reported. The underlying mechanism for the drop in ATP was the strong decrease in intracellular 10-formyltetrahydrofolate, a substrate in two reactions of the de novo purine pathway. Overall, we have demonstrated that p21 can activate G1 or G2 arrest in the absence of DNA damage as a response to metabolite deprivation. In the case of FDH-related metabolic alterations, this response delays apoptosis but is not sufficient to prevent cell death.

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“…In our previous papers we showed that the both adenovirally mediated p53 and p21 overexpression inhibited the growth of several cell lines Kraljevic Pavelic et al 2008). However, p53 was more potent in growth inhibition and apoptosis induction of human tumor cells with non-functional p53.…”

Section: Introductionmentioning

confidence: 97%