Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status

Hideaki Ito, Takao Kanzawa, Toru Miyoshi, Satoshi Hirohata, Satoru Kyo, Arifumi Iwamaru, Hiroshi Aoki, Yasuko Kondo, Seiji Kondo

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wild-type p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

Original languageEnglish
Pages (from-to)685-698
Number of pages14
JournalHuman Gene Therapy
Volume16
Issue number6
DOIs
Publication statusPublished - Jun 2005

Fingerprint

Glioma
Apoptosis
Therapeutics
Neoplasms
Telomerase
p53 Genes
Caspase 6
Caspase 8
Tumor Suppressor Genes
Nude Mice
Caspase 3
Genetic Therapy

ASJC Scopus subject areas

  • Genetics

Cite this

Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status. / Ito, Hideaki; Kanzawa, Takao; Miyoshi, Toru; Hirohata, Satoshi; Kyo, Satoru; Iwamaru, Arifumi; Aoki, Hiroshi; Kondo, Yasuko; Kondo, Seiji.

In: Human Gene Therapy, Vol. 16, No. 6, 06.2005, p. 685-698.

Research output: Contribution to journalArticle

Ito, H, Kanzawa, T, Miyoshi, T, Hirohata, S, Kyo, S, Iwamaru, A, Aoki, H, Kondo, Y & Kondo, S 2005, 'Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status', Human Gene Therapy, vol. 16, no. 6, pp. 685-698. https://doi.org/10.1089/hum.2005.16.685
Ito, Hideaki ; Kanzawa, Takao ; Miyoshi, Toru ; Hirohata, Satoshi ; Kyo, Satoru ; Iwamaru, Arifumi ; Aoki, Hiroshi ; Kondo, Yasuko ; Kondo, Seiji. / Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status. In: Human Gene Therapy. 2005 ; Vol. 16, No. 6. pp. 685-698.
@article{b36fe26ee0cd46f39c1db3b683831778,
title = "Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status",
abstract = "Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wild-type p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.",
author = "Hideaki Ito and Takao Kanzawa and Toru Miyoshi and Satoshi Hirohata and Satoru Kyo and Arifumi Iwamaru and Hiroshi Aoki and Yasuko Kondo and Seiji Kondo",
year = "2005",
month = "6",
doi = "10.1089/hum.2005.16.685",
language = "English",
volume = "16",
pages = "685--698",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "6",

}

TY - JOUR

T1 - Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status

AU - Ito, Hideaki

AU - Kanzawa, Takao

AU - Miyoshi, Toru

AU - Hirohata, Satoshi

AU - Kyo, Satoru

AU - Iwamaru, Arifumi

AU - Aoki, Hiroshi

AU - Kondo, Yasuko

AU - Kondo, Seiji

PY - 2005/6

Y1 - 2005/6

N2 - Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wild-type p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

AB - Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wild-type p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

UR - http://www.scopus.com/inward/record.url?scp=20844439556&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20844439556&partnerID=8YFLogxK

U2 - 10.1089/hum.2005.16.685

DO - 10.1089/hum.2005.16.685

M3 - Article

VL - 16

SP - 685

EP - 698

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 6

ER -