p28-Mediated Activation of p53 in G2–M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy

Yamada, Tohru; Gupta, Tapas K. Das; Beattie, Craig W.

doi:10.1158/0008-5472.can-15-2355

Cited by 67 publications

(44 citation statements)

References 49 publications

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“…Cell-cycle and EMT transition are the key factors that regulate tumor cell growth, metastasis, and chemoresistance (38)(39)(40)(41). The biological effects of miR-296-3p identified in this investigation provide a mechanism for its role in carcinogenesis.…”

Section: Discussionmentioning

confidence: 73%

miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma

Song

Liu

et al. 2017

Clinical Cancer Research

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This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance. The miR-296-3p expression was examined by real-time PCR and hybridization. MTT, EdU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance; Western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and coimmunoprecipitation combined with mass spectrometry and GST pull-down were respectively designed to analyze the DNA-protein complex and HDGF/DDX5/β-catenin complex. We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to cisplatin (DDP) and Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK-Ras-c-Myc signaling, thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF-β-catenin-c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA-FAK-Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin-c-Myc, which suppresses miR-296-3p and further activates PRKCA-FAK-Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with HDGF/DDX5, but not PRKCA. Our study provides a novel mechanism that the miR-296-3p-PRKCA-FAK-Ras-c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC. .

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Section: Discussionmentioning

confidence: 73%

miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma

Song

Liu

et al. 2017

Clinical Cancer Research

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“…In the present study, we selected Raji as our cancerous cell line because of its mutant p53 status. The p53 protein in Raji cell line, has a mutation in its residue 213, while this mutation has no interference with p28 -p53 complex formation (23,32). The cytotoxicity evaluation by MTT assay revealed that p28 peptide strongly inhibited the proliferation of Raji cells, while it had minimal effects on the noncancerous HEK-293 cells.…”

Section: Discussionmentioning

confidence: 99%

“…The p28, a peptide fragment of azurin, has shown specific cell penetration and anti-proliferative effects in cancer cells, similar to the whole protein; however, it does not provoke immunogenic responses (9,17,21). Several studies have reported that p28 forms a complex with either the DBD or NH2-terminal domain of p53 and elevates its intracellular concentration (18,23). These studies emphasize that the p28-mediated elevation of p53 cellular levels occurs rather post-translationally and mainly to a reduction in the activity of proteasome (4,6,7,18).…”

Section: Discussionmentioning

confidence: 99%

“…The antitumor proficiency of p28 is assessed on a variety of cancerous cells in pre-clinical studies (9,17,22). These investigations have revealed that p28 can induce a G2-M interphase arrest in the cell cycle (23). Apart from its impact on the status of p53 and CDK-inhibitors, p28 also functions in non-p53-mediated mechanisms to inhibit tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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Construction, Expression, and Purification of p28 as a Cell-Penetrating Peptide ‎with Anticancer Effects on Burkitt’s Lymphoma Cell Line

et al. 2019

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Background:The p28 is a small-sized cell-penetrating peptide derived from bacterial protein azurin and can function as a cancerspecific anti-proliferative agent. It can penetrate cancer tissues easily without involving the immune system, and increase the intracellular concentration of p53. Objectives: In this study, we have expressed and purified recombinant p28, then evaluated its anti-proliferative and pro-apoptotic effects on Raji cancer cell line. Methods: The p28 gene was amplified and cloned into pTZ57R cloning vector and was sequenced subsequently. Afterward, it was transformed into E. coli BL21 bacterial host by using pET-28a expression vector. Peptide purification was carried out using Ni-NTA chromatography system. Bradford, SDS-PAGE, and western blotting assays were applied to assess the concentration and expression level of the recombinant peptide. The proficiency of p28 in inhibition of tumor growth and induction of apoptosis in cancerous cells was investigated by evaluating the Raji and HEK-293 cells treated with different concentrations of p28. Results: The overexpression of the p28 peptide in the bacterial host was confirmed by SDS-PAGE and western blotting. Moreover, Bradford assay revealed desirable concentrations of the recombinant p28 before and after dialysis. The MTT and PE-Annexin V apoptosis assays indicated the specific function of p28 in impeding the proliferation of cancerous cells and triggering the apoptosis. Conclusions: The p28 induces apoptosis in cancerous cells but not in normal control cells. In summary, p28 is a non-immunogenic small peptide that can penetrate cancerous cells preferentially, impede the cell proliferation, and induce the apoptosis. Overall, these findings suggest p28 as a promising anticancer drug.

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“…Indeed, the p28 peptide was very recently associated to such an increase in the sensitivity to these drugs in different cell models [43], mainly due to its effects of p53 stabilization. Therefore, we tested in parallel both the WT and the F114A mutant protein.…”

Section: Discussionmentioning

confidence: 99%

Azurin interaction with the lipid raft components ganglioside GM-1 and caveolin-1 increases membrane fluidity and sensitivity to anti-cancer drugs

et al. 2018

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Membrane lipid rafts are highly ordered microdomains and essential components of plasma membranes. In this work, we demonstrate that azurin uptake by cancer cells is, in part, mediated by caveolin-1 and GM-1, lipid rafts' markers. This recognition is mediated by a surface exposed hydrophobic core displayed by azurin since the substitution of a phenylalanine residue in position 114 facing the hydrophobic cavity by alanine impacts such interactions, debilitating the uptake of azurin by cancer cells. Treating of cancer cells with azurin leads to a sequence of events: alters the lipid raft exposure at plasma membranes, causes a decrease in the plasma membrane order as examined by Laurdan two-photon imaging and leads to a decrease in the levels of caveolin-1. Caveolae, a subset of lipid rafts characterized by the presence of caveolin-1, are gaining increasing recognition as mediators in tumor progression and resistance to standard therapies. We show that azurin inhibits growth of cancer cells expressing caveolin-1, and this inhibition is only partially observed with mutant azurin. Finally, the simultaneous administration of azurin with anticancer therapeutic drugs (paclitaxel and doxorubicin) results in an enhancement in their activity, contrary to the mutated protein.

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p28-Mediated Activation of p53 in G2–M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy

Cited by 67 publications

References 49 publications

miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma

miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma

Construction, Expression, and Purification of p28 as a Cell-Penetrating Peptide ‎with Anticancer Effects on Burkitt’s Lymphoma Cell Line

Azurin interaction with the lipid raft components ganglioside GM-1 and caveolin-1 increases membrane fluidity and sensitivity to anti-cancer drugs

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