Expression of p21 and mutant p53 gene products in residual prostatic tumor cells after radical radiotherapy

ABSTRACT More than 50% of human cancers contain p53 gene mutations and as a result accumulate altered forms of the full-length p53 protein. Although certain tumor types expressing mutant p53 protein have a poor prognostic process, the precise role of mutant p53 protein in highly malignant tumor cells is not well defined. Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a Fas-binding protein that activates stress-inducible kinase pathways. Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH2-terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently, mutant p53 is able to rescue cells from Daxx-dependent inhibition of proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute to tumorigenesis by inhibiting stress-inducible kinase pathways.

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Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53

Molecules ◽

10.3390/molecules26061637 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1637

Author(s):

Solida Long ◽

Joana B. Loureiro ◽

Carla Carvalho ◽

Luís Gales ◽

Lucília Saraiva ◽

...

Keyword(s):

Growth Inhibition ◽

Small Molecules ◽

Tumor Cells ◽

Mutant P53 ◽

Wild Type ◽

Naturally Occurring ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Amino Derivatives ◽

Carbazole Alkaloids

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

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Supercritical Fluid Extraction of Citrus iyo Hort. ex Tanaka Pericarp Inhibits Growth and Induces Apoptosis Through Abrogation of STAT3 Regulated Gene Products in Human Prostate Cancer Xenograft Mouse Model

Integrative Cancer Therapies ◽

10.1177/1534735416649659 ◽

2016 ◽

Vol 16 (2) ◽

pp. 227-243 ◽

Cited By ~ 2

Author(s):

Chulwon Kim ◽

Il Ho Lee ◽

Ho Bong Hyun ◽

Jong-Chan Kim ◽

Rajendra Gyawali ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Cellular Proliferation ◽

Human Prostate ◽

Parp Cleavage ◽

G1 Arrest ◽

Gene Products ◽

Human Prostate Cancer ◽

Male Mice

Activation of signal transducer and activator of transcription 3 (STAT3) is well known to play a major role in the cell growth, survival, proliferation, metastasis, and angiogenesis of various cancer cells. Most of the citrus species offer large quantities of phytochemicals that have beneficial effects attributed to their chemical components. Our study was carried out to evaluate the anticancer effects of the pericarp of Iyokan ( Citrus iyo Hort. ex Tanaka), locally known as yeagam in Korea, through modulation of the STAT3 signaling pathway in both tumor cells and a nude mice model. The effect of supercritical extracts of yeagam peel (SEYG) on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of SEYG on the growth of DU145 human prostate xenograft tumors in athymic nu/nu male mice was also investigated. We found SEYG exerted substantial inhibitory effect on STAT3 activation in human prostate cancer DU145 cells as compared to other tumor cells analyzed. SEYG inhibited proliferation and downregulated the expression of various STAT3-regulated gene products such as bcl-2, bcl-xL, survivin, IAP-1/2, cyclin D1, cyclin E, COX-2, VEGF, and MMP-9. This correlated with an increase in apoptosis as indicated by an increase in the expression of p53 and p21 proteins, the sub-G1 arrest, and caspase-3-induced PARP cleavage. When administered intraperitoneally, SEYG reduced the growth of DU145 human prostate xenograft tumors through downmodulation of STAT3 activation in athymic nu/nu male mice. Overall, these results suggest that SEYG extract has the potential source of STAT3 inhibitors that may have a potential in chemoprevention of human prostate cancer cells.

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A Mouse Erythroleukemia Cell Line Possessing Friend Spleen Focus-forming Virus gp55 Transgene and Temperature-sensitive Mutant p53 Gene

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1995.tb03052.x ◽

1995 ◽

Vol 86 (3) ◽

pp. 284-291 ◽

Cited By ~ 2

Author(s):

Xin Xu ◽

Yasuko Yamamura ◽

Teruyo Tsukada ◽

Mitsuaki A. Yoshida ◽

Hisato Senda ◽

...

Keyword(s):

Cell Line ◽

P53 Gene ◽

Temperature Sensitive ◽

Mutant P53 ◽

Sensitive Mutant ◽

Temperature Sensitive Mutant ◽

Erythroleukemia Cell ◽

Mouse Erythroleukemia

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Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity

Molecular and Cellular Biology ◽

10.1128/mcb.00375-18 ◽

2018 ◽

Vol 39 (4) ◽

Cited By ~ 3

Author(s):

Leixiang Yang ◽

Tanjing Song ◽

Qian Cheng ◽

Lihong Chen ◽

Jiandong Chen

Keyword(s):

Tumor Cells ◽

Recent Work ◽

Intramolecular Interaction ◽

E3 Ligase ◽

Mutant P53 ◽

Wild Type ◽

Gain Of Function ◽

Core Domain ◽

Acidic Domain ◽

Wild Type P53

ABSTRACT Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53 and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells.

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Tumor Eradication by Wild-type p53-specific Cytotoxic T Lymphocytes

Journal of Experimental Medicine ◽

10.1084/jem.186.5.695 ◽

1997 ◽

Vol 186 (5) ◽

pp. 695-704 ◽

Cited By ~ 149

Author(s):

Michel P.M. Vierboom ◽

Hans W. Nijman ◽

Rienk Offringa ◽

Ellen I.H. van der Voort ◽

Thorbald van Hall ◽

...

Keyword(s):

T Lymphocytes ◽

Tumor Cells ◽

Cytotoxic T Lymphocytes ◽

Normal Tissue ◽

P53 Protein ◽

P53 Gene ◽

Wild Type ◽

Wild Type P53 ◽

Tumor Outgrowth ◽

Tumor Eradication

The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 −/−) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

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