Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway

Li, Yin; Mao, Yuan; Brandt‐Rauf, Paul W.; Williams, Ann C.; Fine, Robert L.

doi:10.1158/1535-7163.mct-04-0206

Cited by 50 publications

(33 citation statements)

References 39 publications

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“…PRIMA-1 is the only compound among 45 tested anticancer agents that selectively induced apoptosis of cell lines with p53 mutation (Bykov et al, 2002a;Li et al, 2005). In our study, PRIMA-1 reduced CXCR4 expression and invasion of breast cancer cells with mutated p53.…”

Section: Discussionsupporting

confidence: 46%

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion

et al. 2006

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Chemokine receptor CXCR4 and its ligand CXCL12 are suggested to be involved in migration, invasion and metastasis of breast cancer cells. Mutation of the tumor suppressor gene p53 in breast cancer is associated with metastasis and aggressive clinical phenotype. In this report, we demonstrate that wild type but not the dominant-negative mutant (V143A) or cancer-specific mutants (R175H or R280K) of p53 repress CXCR4 expression. Recently described cancer-specific p53 isoform, D133p53, also failed to repress CXCR4 promoter activity. Short-interfering RNA-mediated depletion of p53 increased endogenous CXCR4 expression in MCF-7 breast cancer cells that contain wild-type p53. Basal CXCR4 promoter activity in HCT116 colon carcinoma cells deleted of p53 [HCT116(p53KO)] was 10-fold higher compared to that in parental HCT116 cells with functional wild-type p53. Deletion analysis of CXCR4 promoter identified a seven-base pair p53-repressor element homologous to cyclic AMP/AP-1 response (CRE/AP-1) element. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed binding of ATF-1 and cJun to the CRE/AP-1 element. The p53 rescue drug PRIMA-1 reduced CXCR4 mRNA and cell surface expression in MDA-MB-231 cells, which express R280K mutant p53. CP-31398, another p53 rescue drug, similarly reduced cell surface levels of CXCR4. PRIMA-1-mediated decrease in CXCR4 expression correlated with reduced invasion of MDA-MB-231 cells through matrigel. These results suggest a mechanism for elevated CXCR4 expression and metastasis of breast cancers with p53 mutations or isoform expression. We propose that p53 rescue drugs either alone or in combination with chemotherapeutic drugs may be effective in reducing CXCR4-mediated metastasis.

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Section: Discussionsupporting

confidence: 46%

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion

et al. 2006

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“…PRIMA-1 may in fact induce apoptosis via multiple pathways, as it can also trigger mutant p53-dependent apoptosis in the absence of transcription or de novo protein synthesis, or even a cell nucleus (Chipuk et al, 2003). This notion is further supported by studies showing that PRIMA-1 induces apoptosis via the c-Jun-NH2-kinase (JNK) pathway (Li et al, 2005).…”

Section: Small Molecules That Target Mutant P53mentioning

confidence: 92%

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

2007

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“…Most of the solid tumours in humans are deficient in p53 or in some of the modulators involved in p53-related functions; thus, it is possible that the treatment of different types of cancer cells with triptolide induces apoptosis through the JNK pathway, thus explaining the mechanism of the killing of cancer cells that has been demonstrated for this natural product. Similarly, drugs such as PRIMA have been shown to induce cell death in p53-mutated cancer cell lines through a JNK pathway (Li et al, 2005). Therefore, to search for possible targets for future cancer therapies, it will be important to determine if p53-deficient cancer cells are more susceptible to apoptosis than normal cells when TFIIH is affected.…”

Section: Dp53 Physically Interacts With the Dmp52 Subunit Of Tfiihmentioning

confidence: 99%

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

Villicaña¹,

Cruz²,

Zurita³

2013

Journal of Cell Science

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SummaryTranscription factor IIH (TFIIH) participates in transcription, nucleotide excision repair and the control of the cell cycle. In the present study, we demonstrate that the Dmp52 subunit of TFIIH in Drosophila physically interacts with the fly p53 homologue, Dp53. The depletion of Dmp52 in the wing disc generates chromosome fragility, increases apoptosis and produces wings with a reduced number of cells; cellular proliferation, however, is not affected. Interestingly, instead of suppressing the apoptotic phenotype, the depletion of Dp53 in Dmp52-depleted wing disc cells increases apoptosis and the number of cells that suffer from chromosome fragility. The apoptosis induced by the depletion of Dmp52 alone is partially dependent on the JNK pathway. In contrast, the enhanced apoptosis caused by the simultaneous depletion of Dp53 and Dmp52 is absolutely JNK-dependent. In this study, we also show that the anti-proliferative drug triptolide, which inhibits the ATPase activity of the XPB subunit of TFIIH, phenocopies the JNK-dependent massive apoptotic phenotype of Dp53-depleted wing disc cells; this observation suggests that the mechanism by which triptolide induces apoptosis in p53-deficient cancer cells involves the activation of the JNK death pathway.

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Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway

Abstract: PRIMA-1 (p53 reactivation and induction

Cited by 50 publications

References 39 publications

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

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