Effect of aberrant p53 function on temozolomide sensitivity of glioma cell lines and brain tumor initiating cells from glioblastoma

Blough, Michael; Beauchamp, Desiree; Westgate, Morgan R.; Kelly, John J.; Cairncross, J. Gregory

doi:10.1007/s11060-010-0283-9

Cited by 85 publications

(73 citation statements)

References 18 publications

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“…19 Mutant p53 has been shown to induce radiochemotherapy resistance in many cancer types including GBM, 24 with altered p53 expression resulting in increased sensitivity to temozolomide in one experimental model. 3 Reasons for the lack of a clear correlation of p53 with prognosis are many-fold, including the complexity of the p53 signaling pathway, the importance of other regulators in the p53 pathway that may be altered in GBM (for example, Rb, MDM2), and the heterogeneity of p53 mutation types and effects. 12 In fact, methods to target p53 in clinical trials have also been limited by these issues.…”

Section: 32mentioning

confidence: 99%

A practical review of prognostic correlations of molecular biomarkers in glioblastoma

Karsy

Neil

Guan

et al. 2015

FOC

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Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6-methylgua-nine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed.

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Section: 32mentioning

confidence: 99%

A practical review of prognostic correlations of molecular biomarkers in glioblastoma

Karsy

Neil

Guan

et al. 2015

FOC

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“…The role of p53 in temozolomide resistance is far from being understood. Although several groups reported that p53 status is not predictive of response to chemotherapy with alkylating agents (18,21), more recent works suggest that the absence of a functional p53 increases temozolomide sensitivity in glioma cell lines (22) and in intracranial glioblastoma xenografts (23). A trend toward an increased temozolomide sensitivity in patients with p53 mutations was also suggested (24).…”

Section: Discussionmentioning

confidence: 99%

Integrin α5β1 Plays a Critical Role in Resistance to Temozolomide by Interfering with the p53 Pathway in High-Grade Glioma

et al. 2012

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Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the a5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the a5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of a5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the a5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, a5b1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high a5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between a5b1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that a5b1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of a5b1 integrin. Cancer Res; 72(14); 3463-70. Ó2012 AACR.

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“…Blough et al delineated that traditional glioma cell lines that did not express a functional p53 were significantly more sensitive to TMZ than cell lines with functionally intact wild-type p53 expression. RNAi specific for p53 had little effect on sensitivity in p53 null glioma cells (21). Thus, we examined whether low expression of miR-221/222 can sensitize the effects of TMZ in different p53 status glioma cells.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR-221/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of p53 status

Chen

Zhang²,

Han³

et al. 2011

Oncol Rep

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Abstract.A previous study showed that miR-221/222 can regulate cell apoptosis. p53 is a well known tumor suppressor which can influence the chemosensitivity of glioma cells. However, the effect of miR-221/222 in gliomas with different p53 status is unknown. Here, we demostrate that knockdown of miR-221/222 increases apoptosis in human gliomas of different p53 types (U251 cells, p53 mutant-type; LN308 cells, p53 null-type; and U87 cells, p53 wild-type). Furthermore, the effect of miR-221/22 caused no change of p53 expression in the glioma cells studied. In addition, when a specific siRNA against p53 was employed in U87 cells, no attenuation of apoptosis was found after knockdown of miR-221/222. Importantly, we found that As-miR-221/222-treated cells increased expression of Bax, cytochrome c, Apaf-1 and cleaved-caspase-3. Our results showed that low expression of miR-221/222 sensitized glioma cells to temozolomide (TMZ); in addition, ectopic expression of PUMA by pcDNA-PUMA had a similar effect. Taken together, our study indicates that downregulated miR-221/222 can sensitize glioma cells to TMZ by regulating apoptosis independently of p53 status. IntroductionGlioblastoma, the most aggressive type of tumor arising in the central nervous system (CNS), is considered to be one of the deadliest of human cancers. Despite the advances in surgery, radiation therapy, and chemotherapy, the 1-year overall survival rate is less than 30%, and the median survival time of patients with high-grade glioma is only approximately 15 months (1,2). To develop more optimized and effective treatment strategies for glioblastomas, it is critical to gain deeper understanding of the molecular mechanisms underlying gliomagenesis and to identify targets for therapeutic intervention (3,4).MicroRNAs are small regulatory RNA molecules that in recent years have been identified in the progression of various cancers and proposed as novel targets for anticancer therapies (5,6). By negatively regulating their mRNA targets to either degradation or translational repression, they can act as both tumor suppressors and oncogenes (7). Recent studies showed frequent deregulation of miR-221/222 in glioblastoma and astrocytoma cell lines (8). Overexpression of miR-221/222 increased glioma cell proliferation and invasion in vitro and induced glioma growth in a subcutaneous mouse model (9). In addition, blockade of miR-221/222 cluster suppressed human glioma cell growth, suggesting the cosuppression of miR-221/222 cluster might be a potential therapeutic strategy in glioma (10). Our previous study demostrated that miR-221/222 can directly target PUMA inducing apoptosis (11). p53, an upstream gene of PUMA, is a well known tumor-suppressor. However, the role of miR-221/222 in glioma of different p53 status is not well elucidated.In this study, we identified the involvement of miR-221/-222 in mediating apoptosis in glioma regardless of p53 status. Furthermore, we confirmed that low expression of miR-221/222 sensitizes glioma cells to the alkylating agent TMZ partly...

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Effect of aberrant p53 function on temozolomide sensitivity of glioma cell lines and brain tumor initiating cells from glioblastoma

Cited by 85 publications

References 18 publications

A practical review of prognostic correlations of molecular biomarkers in glioblastoma

A practical review of prognostic correlations of molecular biomarkers in glioblastoma

Integrin α5β1 Plays a Critical Role in Resistance to Temozolomide by Interfering with the p53 Pathway in High-Grade Glioma

Downregulation of miR-221/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of p53 status

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