Loss of heterozygosity at 17p13.3-ter, distal to TP53, correlates with negative hormonal phenotype in sporadic breast cancer

Roncuzzi, Laura; Brognara, Irene; Baiocchi, Daniela; Amadori, Dino; Gasperi‐Campani, Anna

doi:10.3892/or.14.2.471

Cited by 10 publications

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“…Two different assays were used to determine cell death, DNA fragmentation and DAPI staining. For DNA fragmentation, following incubation with the designated concentrations of the drug, 1x10 6 cells were pelleted and the total genomic DNA was extracted and purified as previously described (20). Apoptosis was assessed by DNA fragmentation using an ApoAlert LM-PCR ladder assay kit according to the manufacturer's instructions (Clontech, CA).…”

Section: Methodsmentioning

confidence: 99%

Effect of Vinorelbine on cell growth and apoptosis induction in human osteosarcoma in vitro

et al. 2006

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Abstract. Vinorelbine (VNR) is a semi-synthetic vinca alkaloid known to exert its antitumour activity by interfering with the polymerisation of tubulin. It has shown a broad spectrum of activity in some advanced carcinomas of lung, breast and ovary. This report demonstrates for the first time the antiproliferative effect of VNR and its molecular mechanism in human osteosarcoma in vitro. TP53 wild-type HOS cells and TP53 mutated MG-63 cells were chosen for this study. In each cell line, VNR caused a significant dose-and time-dependent growth inhibition and induced apoptotic death independent of TP53 status. Phosphorylation and/or alteration of Bcl-2 were not induced by VNR, thereby indicating a new pathway utilised by the drug to induce apoptosis in this tumour in vitro. VNR produced a down-regulation of cyclin D1 and an upregulation of p53 expression in TP53 wild-type HOS cells, whereas no alteration in cyclin D1 expression was evident in the TP53 negative MG-63 cells. These data suggest a new potential use for Vinorelbine as a therapeutic agent against human osteosarcoma. IntroductionOsteosarcoma (OS) is the most frequent malignant bone tumour with a peak incidence in the second and third decade of life (1). As a result of the introduction of neoadjuvant chemotherapy, an improvement in the long-term survival rate from 10% to nearly 70% has been achieved (2). At present, osteosarcoma patients receive full neoadjuvant multi-agent chemotherapy immediately after diagnosis. Initial tumour size and detectable metastases at diagnosis are prognostic factors and serve together with the response to chemotherapy as a basis for the risk adapted postoperative therapy factor (3,4). Despite the improved survival rate, drug resistance is still one of the major problems in the treatment of this cancer (5). Alterations in the TP53 gene are frequent in human osteosarcoma cells and have been associated with resistance to chemotherapy as well as with poor prognosis in this malignancy (6,7). Pompetti et al (8) correlated TP53 mutations with a lack of therapy-induced apoptosis, while studies by Goto et al (9) demonstrated an association between loss of heterozygosity at TP53 locus and chemoresistance in human osteosarcoma.Different studies indicate that cells lacking a p53 function may present a higher sensitivity to anticancer drugs that induce DNA damage and to the cytotoxic effects of antimicrotubule agents (10-12). Vinorelbine (VNR) is a semisynthetic vinca alkaloid which binds to · and ß tubulin, thus inhibiting microtubule assembly and impairing metaphasic tumour cell division. Compared with different vinca alkaloids, VNR shows markedly improved clinical efficacy and reduced toxicity (13). This drug is now widely used and licensed for the treatment of non-small cell lung cancer, breast cancer and ovarian cancer (14) and shows promise in relapsed or refractory Hodgkin's disease (15) and prostatic carcinoma (16). Like other antimicrotubule agents, VNR is known to be a promoter of apoptosis in cancer cells. The precise mechanism b...

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Section: Methodsmentioning

confidence: 99%

Effect of Vinorelbine on cell growth and apoptosis induction in human osteosarcoma in vitro

et al. 2006

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“…A minimal region of recurrent deletion/allelic loss distal to the Tp53 gene was identified in an experimental rat model for endometrial carcinoma [ 1 ]. Deletions at the homologous position on human chromosome 17 (17p13.3) unassociated with TP53 mutation have been reported in several types of human tumors [ 2 – 5 ], suggesting a tumor suppressor activity in this chromosomal region. In deletion mapping, combined with gene expression, sequencing and epigenetic silencing, the candidate region was delimited and Myo1c was identified as one of the most likely candidates for the proposed tumor suppressor activity [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Lowered Expression of Tumor Suppressor Candidate MYO1C Stimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT

et al. 2016

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Myosin-1C (MYO1C) is a tumor suppressor candidate located in a region of recurrent losses distal to TP53. Myo1c can tightly and specifically bind to PIP2, the substrate of Phosphoinositide 3-kinase (PI3K), and to Rictor, suggesting a role for MYO1C in the PI3K pathway. This study was designed to examine MYO1C expression status in a panel of well-stratified endometrial carcinomas as well as to assess the biological significance of MYO1C as a tumor suppressor in vitro. We found a significant correlation between the tumor stage and lowered expression of MYO1C in endometrial carcinoma samples. In cell transfection experiments, we found a negative correlation between MYO1C expression and cell proliferation, and MYO1C silencing resulted in diminished cell migration and adhesion. Cells expressing excess of MYO1C had low basal level of phosphorylated protein kinase B (PKB, a.k.a. AKT) and cells with knocked down MYO1C expression showed a quicker phosphorylated AKT (pAKT) response in reaction to serum stimulation. Taken together the present study gives further evidence for tumor suppressor activity of MYO1C and suggests MYO1C mediates its tumor suppressor function through inhibition of PI3K pathway and its involvement in loss of contact inhibition.

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“…Approximately 50% of all human malignancies harbor mutations or deletions in the TP53 gene that disable the tumor suppressor function of the encoded protein [4,5]. Most other human cancers express wild-type p53 protein but encode alternate defects in the p53 signaling pathway that play critical roles in tumorigenesis [4][5][6].…”

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Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation

Shukla

Gupta

2008

Free Radical Biology and Medicine

142

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Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10-80 μM) of apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14 ARFmediated downregulation of MDM2 protein, inhibition of NF-κB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose-and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-α, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from apigenin-induced apoptosis. In vivo, apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways. KeywordsReactive oxygen species; Apoptosis; p53; Prostate cancer; Apigenin; Free radicals Cancer prevention is profoundly dependent on the p53 tumor suppressor protein, as it functions in regulating cellular growth and protecting cells from malignant transformation [1,2]. Several studies have demonstrated the anticancer activities of p53, and in fact, p53 is the most *Corresponding author. Department of Urology, Case Western Reserve University, Cleveland, OH 44106, USA. Fax: +1 216 368 0213. E-mail address: sanjay.gupta@case.edu (S. Gupta). This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright NIH Public Access NIH-PA Author ManuscriptNIH-PA A...

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Loss of heterozygosity at 17p13.3-ter, distal to TP53, correlates with negative hormonal phenotype in sporadic breast cancer

Cited by 10 publications

References 0 publications

Effect of Vinorelbine on cell growth and apoptosis induction in human osteosarcoma in vitro

Effect of Vinorelbine on cell growth and apoptosis induction in human osteosarcoma in vitro

Lowered Expression of Tumor Suppressor Candidate MYO1C Stimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT

Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation

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