Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer

Sasaki, Yasushi; Morimoto, Ichiro; Ishida, Setsuko; Yamashita, Toshiharu; Imai, Kohzoh; Tokino, Takashi

doi:10.1038/sj.gt.3301538

Cited by 57 publications

(43 citation statements)

References 33 publications

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“…Direct sequencing was carried out to verify the integrity of the inserted DNA sequences. Procedures used to generate, purify and infect replication-deficient CHFR-containing recombinant adenoviruses (Ad-CHFR) have been described earlier (Sasaki et al, 2001;Satoh et al, 2003). A recombinant adenovirus containing the enhanced green fluorescent proteins (EGFP) gene (Ad-EGFP) was generated as a control.…”

Section: Plasmids and Recombinant Adenovirusesmentioning

confidence: 99%

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

et al. 2009

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The mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger domains) is silenced in various human cancers by promoter hypermethylation, suggesting that CHFR is a tumor suppressor. Here, we show that CHFR functions as a negative regulator of the nuclear factor-jB (NF-jB) pathway. Expression of CHFR inhibited NF-jB reporter activity, whereas knockdown of CHFR activated reporter activity. These activities are independent of its RING finger domain. Furthermore, we found that CHFR physically interacts with p65 in cells. Electrophoretic mobility shift assays (EMSAs) and ELISA-based NF-jB-binding assays showed that CHFR negatively regulated transcriptional activity of p65. In addition, our data show that interleukin (IL)-8 is significantly downregulated by CHFR, and that the migration of human endothelial cells is suppressed in culture medium conditioned from CHFR-expressing cancer cells. Using a xenograft model, we show that neovascularization is suppressed by adenovirus-mediated transfer of CHFR. These results indicate that expression of CHFR markedly reduces the expression of IL-8 through the inhibition of NF-jB. As the NF-jB signaling pathway plays a critical role in the development and progression of cancer, our findings show the functional relationship between epigenetic alteration and inflammation/angiogenesis in human cancer cells, thereby showing several potential targets for therapeutic intervention.

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Section: Plasmids and Recombinant Adenovirusesmentioning

confidence: 99%

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

et al. 2009

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“…20 Another independent study demonstrated the potential therapeutic use of p73 expressing adenovirus against colorectal cancer cells. 21 In the present study, we investigated the cytotoxic potential of a replicationdeficient recombinant adenovirus expressing p73b (Adp73) against a panel of human cancer cell lines of diverse tissue origin. We analyzed the infectivity of Ad-p73 by monitoring the cellular p73 and p21 WAF1/CIP1 levels as well as the cytotoxicity against a variety of cancer cells.…”

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confidence: 99%

p73β-expressing recombinant adenovirus: a potential anticancer agent

et al. 2005

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Tumor suppressor p53-based gene therapy strategy is ineffective in certain conditions. p73, a p53 homologue, could be a potential alternative gene therapy agent as it has been found to be an important determinant of chemosensitivity in cancer cells. Previously, we have reported the generation of a replication-deficient adenovirus expressing p73b (Ad-p73). In this study, we evaluated the therapeutic potential of Ad-p73 against a panel of cancer cells (n ¼ 12) of different tissue origin. Ad-p73 infected all the cell lines tested very efficiently resulting in several-fold increase in p73b levels, which is also functional as it activated the known target gene p21 WAF1/CIP1 . Infection with Ad-p73 resulted in potent cytotoxicity in all the cell lines tested. The mechanism of p73-induced cytotoxicity in these cell lines is found to be due to a combination of cell cycle arrest and induction of apoptosis. In addition, exogenous overexpression of p73 by Ad-p73 infection increased the chemosensitivity of cancer cells by many fold to commonly used drug adriamycin. Moreover, Ad-p73 is more efficient than Ad-p53 in enhancing the chemosensitivity of mutant p53 harboring cells. Furthermore, Ad-p73 infection did not induce apoptosis in human normal lung fibroblasts (HEL 299) and human immortalized keratinocytes (HaCaT). These results suggest that Ad-p73 is a potent cytotoxic agent specifically against cancer cells and could be developed as a cancer gene therapy agent either alone or in combination with chemotherapeutic agents.

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“…[31][32][33] In colon cancer cell lines, TAp63g and TAp73b have the strongest pro-apoptotic potential of all of the p63 and p73 isoforms. 34 We introduced p53, TAp63g and TAp73b into 56 cancer cell lines using an adenoviral vector (Ad) and compared their effects on cell death and apoptosis by using flow cytometry. The sub-G1 fraction (%) contains apoptotic cells.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies reported that p53 family activity correlates with tumor cell sensitivity to certain DNA-damaging agents. 34,[36][37][38][39] In general, gene therapy is given in combination with chemotherapy; p63-53O may have potential as a cancer gene therapy agent either alone or in combination with chemotherapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

A novel approach to cancer treatment using structural hybrids of the p53 gene family

et al. 2012

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The p53 tumor suppressor belongs to a gene family that includes two other structurally and functionally related members: p73 and p63. The regulation of p53 activity differs significantly from that of p73 and p63. To enhance the tumor suppressive activity of p53, we constructed six recombinant adenoviruses that encode hybrid proteins with three functional domains derived from either p53 or TAp63g. The potency of these hybrid molecules in suppressing tumorigenesis was evaluated using in vitro and in vivo models. Of the hybrid molecules tested, one hybrid named p63-53O was the most potent activator of apoptosis in human cancer cells. The p63-53O hybrid is composed of the transcriptional activation domain and DNA-binding domain of TAp63g and the oligomerization domain of p53. The p63-53O hybrid efficiently transactivated p53AIP1. Moreover, silencing of p53AIP1 partially abolished the apoptotic response to p63-53O in human cancer cells. The p53-p63 hybrid molecule is a novel potent anti-proliferative agent for the treatment of cancer.

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Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer

Abstract: p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro)

Cited by 57 publications

References 33 publications

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

p73β-expressing recombinant adenovirus: a potential anticancer agent

A novel approach to cancer treatment using structural hybrids of the p53 gene family

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