Drug-induced Apoptosis and p53, BCL-2 and BAX Expression in Breast Cancer Tissues In Vivo and in Fibroblast Cells In Vitro

Suzuki, Koichi; Kazui, Teruhisa; Yoshida, Masayuki; Uno, Takeji; Kobayashi, Toshihiko; Kimura, Taizo; Yoshida, Teruhiko; Sugimura, Haruhiko

doi:10.1093/jjco/29.7.323

Cited by 29 publications

(17 citation statements)

References 35 publications

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“…and Bcl-2 gene expression has been previously demonstrated in vitro [39] and some authors have confirmed that the down-regulation of Bcl-2 and/or the up-regulation of p53 and p21 are certainly one of the important modes of apoptosis induction by taxanes [30]. Our data obtained after pifithrin α incubation support the notion that VRL treatment triggers p53 activation and leads to a p53-dependent down-regulation of Bcl-2.…”

Section: Discussionsupporting

confidence: 87%

Transcriptional down-regulation of Bcl-2 by vinorelbine: Identification of a novel binding site of p53 on Bcl-2 promoter

Bourgarel-Rey¹,

Savry²,

Hua³

et al. 2009

Biochemical Pharmacology

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To cite this version:Véronique Bourgarel-Rey, Amandine Savry, Guoqiang Hua, Manon Carré, Céline Bressin, et al.. Transcriptional down-regulation of Bcl-2 by vinorelbine: identification of a novel binding site of p53 on Bcl-2 promoter. Biochemical Pharmacology, Elsevier, 2009, 78 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 2 AbstractThe Bcl-2 family contains a panel of proteins which are conserved regulators of apoptosis in mammalian cells, like the anti-apoptotic protein Bcl-2. According to its significant role in altering susceptibility to apoptosis, the deciphering of the mechanism of Bcl-2 expression modulation may be crucial for identifying therapeutics strategies for cancer.Treatment with microtubule -targeting agents, including taxanes and Vinca alkaloids, generally leads to a decrease in Bcl-2 intracellular amounts. Whereas the interest for these chemotherapeutics is accompanied by advances in the fundamental understanding of their anticancer properties, the molecular mechanism underlying changes in Bcl2 expression remains poorly understood. We report here that p53 contributes to vinorelbine-induced Bcl-2 down-regulation. Indeed, the decrease in Bcl-2 protein levels observed during vinorelbineinduced apoptosis was correlated to the decrease in mRNA levels, as a result of the inhibition of Bcl-2 transcription and promoter activity. In this context, we evaluated p53 contribution in the Bcl-2 transcriptional down-regulation. We identified, by chromatin immunoprecipitation, a novel p53 binding site in the Bcl-2 promoter, within a region upstream P 1 promoter. We showed that vinorelbine treatment increased this interaction in A549 cells. This work strengthens the links between p53 and Bcl-2 at a transcriptional level, upon microtubuletargeting agent treatment. Our study also provides answers that will be useful to assess microtubule-targeting agents' mechanism of action and that may help to better understand and increase their effectiveness.

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Section: Discussionsupporting

confidence: 87%

Transcriptional down-regulation of Bcl-2 by vinorelbine: Identification of a novel binding site of p53 on Bcl-2 promoter

Bourgarel-Rey¹,

Savry²,

Hua³

et al. 2009

Biochemical Pharmacology

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“…In various types of malignancies such as breast and hepatocellular cancer, somatostatin has been noted for its induction of apoptosis through the direct pro-apoptotic factor BAX2829. Further, increased BAX/Bcl-2 ratio has been shown in response to SSTR2 mediated apoptosis in pancreatic cancer30.…”

Section: Resultsmentioning

confidence: 99%

Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target

Sizdahkhani

Feldman

Piazza

et al. 2017

Sci Rep

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Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHLHBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX -caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat 68 Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy.Von Hippel-Lindau disease (VHL) is an autosomal-dominant tumor disorder affecting 1 in 36,000 live births 1 due to mutations in the tumor suppressor VHL gene 2 . Up to 80% of patients with VHL develop central nervous system (CNS) hemangioblastomas (HBs) in the infratentorial regions, including the cerebellum and spinal cord, due to somatic 'second hits' at the VHL locus 3,4 . Approximately half of the VHL associated HBs (VHL-HBs) will grow over time and lead to mass effect-related neurological symptoms 5 . Surgical resection of symptomatic VHL-HBs remains the standard-of-care, but even with optimal management VHL-HBs remain a leading cause of death in VHL patients 3,4 . In some cases, surgical resection of symptomatic VHL-HBs is not an option due to unresectable locations or due to extensive co-morbidities. Development of chemotherapy and anti-angiogenic therapy for such patients remains underdeveloped due to the indolent nature of VHL disease [6][7][8][9][10] . Due to relatively long life expectancy of VHL patients 11 , treatment with toxic chemotherapeutic agents is not feasible for extended periods of time. Alternative strategies for long term management of unresectable VHL-HBs may arise from observations that VHL-HBs originate from hematopoietic precursors 12,13 , and that hematopoietic stem cells are known to express somatostatin receptors 14 . Our experience with DOTA-TATE positron emission tomography (PET) imaging of VHL patients confirms previous reports of VHL-HB avidity to somatostatin analogues (Fig. 1A-D) [15][16][17] . However, the therapeutic

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“…Decreased expression of Bcl-2 and increased expression of Bax are correlated with the response to anticancer compounds for chemotherapy in cancer cell lines. In addition, the loss of Bcl-2 expression can promote the induction of apoptosis (27)(28)(29). An anticancer drug that initiates apoptosis may be useful as a new category of chemotherapeutic agent.…”

Section: Discussionmentioning

confidence: 99%

Hesperetin Induced G1-Phase Cell Cycle Arrest in Human Breast Cancer MCF-7 Cells: Involvement of CDK4 and p21

Choi

2007

Nutrition and Cancer

112

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This study was to investigate the effects of hesperetin on cell proliferation and cell cycle arrest and explored the mechanism for these effects in breast carcinoma MCF-7 cells. Hesperetin significantly inhibited cell proliferation in a dose-dependent manner after treatment for 48 and 72 h and resulted in significant cell cycle arrest in the G1 phase. In the G1-phase related proteins, hesperetin downregulates the cyclin-dependent kinases (CDKs) and cyclins and upregulates p21(Cip1) and p27(Kip1) in cells treated with hesperetin for 48 h and 72 h. After 72 h treatment, these phenomenons were more pronounced. Hesperetin treatment at high concentration for 72 h resulted in a decrease in CDK2 and CDK4 together with cyclin D. In addition, hesperetin increases the binding of CDK4 with p21(Cip1) but not p27(Kip1) or p57(Kip2). Taken together, our data suggest for the first time that the regulation of CDK4 and p21(Cip1)1 may participate in the anticancer activity pathway of hesperetin in MCF-7 cells.

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Drug-induced Apoptosis and p53, BCL-2 and BAX Expression in Breast Cancer Tissues In Vivo and in Fibroblast Cells In Vitro

Cited by 29 publications

References 35 publications

Transcriptional down-regulation of Bcl-2 by vinorelbine: Identification of a novel binding site of p53 on Bcl-2 promoter

Transcriptional down-regulation of Bcl-2 by vinorelbine: Identification of a novel binding site of p53 on Bcl-2 promoter

Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target

Hesperetin Induced G1-Phase Cell Cycle Arrest in Human Breast Cancer MCF-7 Cells: Involvement of CDK4 and p21

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