<i>In vitro</i> Drug Response and Molecular Markers Associated with Drug Resistance in Malignant Gliomas

Fruehauf, John P.; Brem, Henry; Brem, Steven; Sloan, Andrew E.; Barger, Geoffrey; Huang, Weidong; Parker, Ricardo J.

doi:10.1158/1078-0432.ccr-05-1830

Cited by 74 publications

(43 citation statements)

References 71 publications

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“…with increased resistance to chemotherapy in many cancers (5,(38)(39)(40). Although the mechanisms underlying the association of wild-type p53 with drug resistance is likely to be complex and to include effects on the cell cycle and altered apoptotic response (41), our data suggest that, in GSTP1-expressing tumors, the ability of p53 to increase GSTP1 expression will be an important part of this mechanism of drug resistance and stress response.…”

Section: Discussionmentioning

confidence: 74%

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Stephenson

Cao

et al. 2008

Molecular Cancer Research

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The glutathione S-transferase P1 (GSTP1) is involved in multiple cellular functions, including phase II metabolism, stress response, signaling, and apoptosis. The mechanisms underlying the significantly high GSTP1 expression in many human tumors are, however, currently not well understood. We report here that the GSTP1 gene is a heretofore unrecognized downstream transcriptional target of the tumor suppressor p53. We identified a p53-binding motif comprising two consecutive half-sites located in intron 4 of the GSTP1 gene and is highly homologous to consensus p53-binding motifs in other p53-responsive genes. Using a combination of electrophoretic mobility shift assay and DNase I footprinting analyses, we showed that wild-type p53 protein binds to the GSTP1 p53 motif and luciferase reporter assays showed the motif to be transcriptionally functional in human tumor cells. In a temperature-sensitive p53-mutant cells, levels of both p21/WAF1 and GSTP1 gene transcripts increased time dependently when cells were switched from the inactive mutant state to the wild-type p53 state. Small interfering RNA -mediated reduction of p53 expression resulted in a specific decrease in GSTP1 expression and in tumor cells with mutated p53; adenovirally mediated expression of wild-type p53 increased GSTP1 expression significantly. In a panel of early-passage brain tumor cultures from patients, high levels of GSTP1 transcripts and protein were associated with wild-type p53 and, conversely, low GSTP1 levels with mutant p53. p53 expression knockdown by small interfering RNA increased cisplatin sensitivity. The ability of wild-type p53 to transcriptionally activate the human GSTP1 gene defines a novel mechanism of protecting the genome and, potentially, of tumor drug resistance. (Mol Cancer Res 2008;6(5):843 -50)

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Section: Discussionmentioning

confidence: 74%

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Stephenson

Cao

et al. 2008

Molecular Cancer Research

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“…Thus, GSTP1 functions as an endogenous molecular regulatory switch that allows the cell to regulate JNK signaling in response to its physiological status and/or different stimuli. A consequence of the dual metabolic and signaling regulatory function is that GSTP1 can mediate the response of both normal and tumor cells to agents regardless of whether or not they are direct GSTP1 substrates (17,29,(33)(34)(35)(36).…”

mentioning

confidence: 99%

Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells

Okamura¹,

Antoun²,

Keir³

et al. 2015

Journal of Biological Chemistry

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Background: GSTP1 is a downstream EGFR phosphorylation target. Results: EGFR-dependent C-terminal Tyr-198 phosphorylation shifts GSTP1 to the monomeric state, facilitates JNK binding and inhibition, and suppresses apoptosis in brain tumor cells. Conclusion: Enhanced suppression of JNK signaling by EGFR-phosphorylated GSTP1 provides a survival advantage for tumors. Significance: The GSTP1-EGFR cross-talk is a mechanism of tumor cell survival and drug resistance.

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“…[15][16][17][18] However, in this process, MGMT is rapidly degraded through the ubiquitin/proteasome pathway after receiving alkyl groups from DNA, and the repletion of cellular MGMT pools depends on resynthesis of the molecule. 19 This makes it a suitable target for intervention in an effort to improve the therapeutic efficacy of TMZ.…”

mentioning

confidence: 99%

Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells

et al. 2010

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Glioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that smallinterfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced gliomainitiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations.

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In vitro Drug Response and Molecular Markers Associated with Drug Resistance in Malignant Gliomas

Cited by 74 publications

References 71 publications

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells

Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells

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