p53-defective tumors with a functional apoptosome-mediated pathway: A new therapeutic target

Tetsuo Mashima, Tomoko Oh-hara, Shigeo Sato, Mikiko Mochizuki, Yoshikazu Sugimoto, Kanami Yamazaki, Jun Ichi Hamada, Mitsuhiro Tada, Tetsuya Moriuchi, Yuichi Ishikawa, Yo Kato, Hiroshi Tomoda, Takao Yamori, Takashi Tsuruo

Research output: Contribution to journalArticle

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Abstract

Background: Although cancer cells appear to maintain the machinery for intrinsic apoptosis, defects in the pathway develop during malignant transformation, preventing apoptosis from occurring. How to specifically induce apoptosis in cancer cells remains unclear. Methods: We determined the apoptosome activity and p53 status of normal human cells and of lung, colon, stomach, brain, and breast cancer cells by measuring cytochrome c-dependent caspase activation and by DNA sequencing, respectively, and we used COMPARE analysis to identify apoptosome-specific agonists. We compared cell death, cytochrome c release, and caspase activation in NCI-H23 (lung cancer), HCT-15 (colon cancer), and SF268 (brain cancer) cells treated with Triacsin c, an inhibitor of acyl-CoA synthetase (ACS), or with vehicle. The cells were mock, transiently, or stably transfected with genes for Triacsin c-resistant ACSL5, dominant negative caspase-9, or apoptotic protease activating factor-1 knockdown. We measured ACS activity and levels of cardiolipin, a mitochondrial phospholipid, in mock and ACSL5-transduced SF268 cells. Nude mice carrying NCI-H23 xenograft tumors (n = 10) were treated with Triacsin c or vehicle, and xenograft tumor growth was assessed. Groups were compared using two-sided Student t tests. Results: Of 21 p53-defective tumor cell lines analyzed, 17 had higher apoptosome activity than did normal cells. Triacsin c selectively induced apoptosome-mediated death in tumor cells (caspase activity of Triacsin c-treated versus untreated SF268 cells; means = 1020% and 100%, respectively; difference = 920%, 95% CI = 900% to 940%; P<.001). Expression of ACSL5 suppressed Triacsin c-induced cytochrome c release and subsequent cell death (cell survival of Triacsin c-treated mock-versus ACSL5-transduced SF268 cells; means = 40% and 83%, respectively; difference = 43%, 95% CI = 39% to 47%; P<.001). ACS was also essential to the maintenance of cardiolipin levels. Finally, Triacsin c suppressed growth of xenograft tumors (relative tumor volume on day 21 of Triacsin c-treated versus untreated mice; means = 4.6 and 9.6, respectively; difference = 5.0, 95% CI = 2.1 to 7.9; P = .006). Conclusions: Many p53-defective tumors retain activity of the apoptosome, which is therefore a potential target for cancer chemotherapy. Inhibition of ACS may be a novel strategy to induce the death of p53-defective tumor cells.

Original languageEnglish
Pages (from-to)765-777
Number of pages13
JournalJournal of the National Cancer Institute
Volume97
Issue number10
DOIs
Publication statusPublished - 2005 May 18

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Apoptosomes
Coenzyme A Ligases
Neoplasms
Therapeutics
Caspases
Cytochromes c
Heterografts
Brain Neoplasms
Cardiolipins
Apoptosis
Colonic Neoplasms
Apoptotic Protease-Activating Factor 1
Lung Neoplasms
Cell Death
Caspase 9
Growth
Tumor Burden
Tumor Cell Line
DNA Sequence Analysis
Nude Mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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p53-defective tumors with a functional apoptosome-mediated pathway : A new therapeutic target. / Mashima, Tetsuo; Oh-hara, Tomoko; Sato, Shigeo; Mochizuki, Mikiko; Sugimoto, Yoshikazu; Yamazaki, Kanami; Hamada, Jun Ichi; Tada, Mitsuhiro; Moriuchi, Tetsuya; Ishikawa, Yuichi; Kato, Yo; Tomoda, Hiroshi; Yamori, Takao; Tsuruo, Takashi.

In: Journal of the National Cancer Institute, Vol. 97, No. 10, 18.05.2005, p. 765-777.

Research output: Contribution to journalArticle

Mashima, T, Oh-hara, T, Sato, S, Mochizuki, M, Sugimoto, Y, Yamazaki, K, Hamada, JI, Tada, M, Moriuchi, T, Ishikawa, Y, Kato, Y, Tomoda, H, Yamori, T & Tsuruo, T 2005, 'p53-defective tumors with a functional apoptosome-mediated pathway: A new therapeutic target', Journal of the National Cancer Institute, vol. 97, no. 10, pp. 765-777. https://doi.org/10.1093/jnci/dji133
Mashima, Tetsuo ; Oh-hara, Tomoko ; Sato, Shigeo ; Mochizuki, Mikiko ; Sugimoto, Yoshikazu ; Yamazaki, Kanami ; Hamada, Jun Ichi ; Tada, Mitsuhiro ; Moriuchi, Tetsuya ; Ishikawa, Yuichi ; Kato, Yo ; Tomoda, Hiroshi ; Yamori, Takao ; Tsuruo, Takashi. / p53-defective tumors with a functional apoptosome-mediated pathway : A new therapeutic target. In: Journal of the National Cancer Institute. 2005 ; Vol. 97, No. 10. pp. 765-777.
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abstract = "Background: Although cancer cells appear to maintain the machinery for intrinsic apoptosis, defects in the pathway develop during malignant transformation, preventing apoptosis from occurring. How to specifically induce apoptosis in cancer cells remains unclear. Methods: We determined the apoptosome activity and p53 status of normal human cells and of lung, colon, stomach, brain, and breast cancer cells by measuring cytochrome c-dependent caspase activation and by DNA sequencing, respectively, and we used COMPARE analysis to identify apoptosome-specific agonists. We compared cell death, cytochrome c release, and caspase activation in NCI-H23 (lung cancer), HCT-15 (colon cancer), and SF268 (brain cancer) cells treated with Triacsin c, an inhibitor of acyl-CoA synthetase (ACS), or with vehicle. The cells were mock, transiently, or stably transfected with genes for Triacsin c-resistant ACSL5, dominant negative caspase-9, or apoptotic protease activating factor-1 knockdown. We measured ACS activity and levels of cardiolipin, a mitochondrial phospholipid, in mock and ACSL5-transduced SF268 cells. Nude mice carrying NCI-H23 xenograft tumors (n = 10) were treated with Triacsin c or vehicle, and xenograft tumor growth was assessed. Groups were compared using two-sided Student t tests. Results: Of 21 p53-defective tumor cell lines analyzed, 17 had higher apoptosome activity than did normal cells. Triacsin c selectively induced apoptosome-mediated death in tumor cells (caspase activity of Triacsin c-treated versus untreated SF268 cells; means = 1020{\%} and 100{\%}, respectively; difference = 920{\%}, 95{\%} CI = 900{\%} to 940{\%}; P<.001). Expression of ACSL5 suppressed Triacsin c-induced cytochrome c release and subsequent cell death (cell survival of Triacsin c-treated mock-versus ACSL5-transduced SF268 cells; means = 40{\%} and 83{\%}, respectively; difference = 43{\%}, 95{\%} CI = 39{\%} to 47{\%}; P<.001). ACS was also essential to the maintenance of cardiolipin levels. Finally, Triacsin c suppressed growth of xenograft tumors (relative tumor volume on day 21 of Triacsin c-treated versus untreated mice; means = 4.6 and 9.6, respectively; difference = 5.0, 95{\%} CI = 2.1 to 7.9; P = .006). Conclusions: Many p53-defective tumors retain activity of the apoptosome, which is therefore a potential target for cancer chemotherapy. Inhibition of ACS may be a novel strategy to induce the death of p53-defective tumor cells.",
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TY - JOUR

T1 - p53-defective tumors with a functional apoptosome-mediated pathway

T2 - A new therapeutic target

AU - Mashima, Tetsuo

AU - Oh-hara, Tomoko

AU - Sato, Shigeo

AU - Mochizuki, Mikiko

AU - Sugimoto, Yoshikazu

AU - Yamazaki, Kanami

AU - Hamada, Jun Ichi

AU - Tada, Mitsuhiro

AU - Moriuchi, Tetsuya

AU - Ishikawa, Yuichi

AU - Kato, Yo

AU - Tomoda, Hiroshi

AU - Yamori, Takao

AU - Tsuruo, Takashi

PY - 2005/5/18

Y1 - 2005/5/18

N2 - Background: Although cancer cells appear to maintain the machinery for intrinsic apoptosis, defects in the pathway develop during malignant transformation, preventing apoptosis from occurring. How to specifically induce apoptosis in cancer cells remains unclear. Methods: We determined the apoptosome activity and p53 status of normal human cells and of lung, colon, stomach, brain, and breast cancer cells by measuring cytochrome c-dependent caspase activation and by DNA sequencing, respectively, and we used COMPARE analysis to identify apoptosome-specific agonists. We compared cell death, cytochrome c release, and caspase activation in NCI-H23 (lung cancer), HCT-15 (colon cancer), and SF268 (brain cancer) cells treated with Triacsin c, an inhibitor of acyl-CoA synthetase (ACS), or with vehicle. The cells were mock, transiently, or stably transfected with genes for Triacsin c-resistant ACSL5, dominant negative caspase-9, or apoptotic protease activating factor-1 knockdown. We measured ACS activity and levels of cardiolipin, a mitochondrial phospholipid, in mock and ACSL5-transduced SF268 cells. Nude mice carrying NCI-H23 xenograft tumors (n = 10) were treated with Triacsin c or vehicle, and xenograft tumor growth was assessed. Groups were compared using two-sided Student t tests. Results: Of 21 p53-defective tumor cell lines analyzed, 17 had higher apoptosome activity than did normal cells. Triacsin c selectively induced apoptosome-mediated death in tumor cells (caspase activity of Triacsin c-treated versus untreated SF268 cells; means = 1020% and 100%, respectively; difference = 920%, 95% CI = 900% to 940%; P<.001). Expression of ACSL5 suppressed Triacsin c-induced cytochrome c release and subsequent cell death (cell survival of Triacsin c-treated mock-versus ACSL5-transduced SF268 cells; means = 40% and 83%, respectively; difference = 43%, 95% CI = 39% to 47%; P<.001). ACS was also essential to the maintenance of cardiolipin levels. Finally, Triacsin c suppressed growth of xenograft tumors (relative tumor volume on day 21 of Triacsin c-treated versus untreated mice; means = 4.6 and 9.6, respectively; difference = 5.0, 95% CI = 2.1 to 7.9; P = .006). Conclusions: Many p53-defective tumors retain activity of the apoptosome, which is therefore a potential target for cancer chemotherapy. Inhibition of ACS may be a novel strategy to induce the death of p53-defective tumor cells.

AB - Background: Although cancer cells appear to maintain the machinery for intrinsic apoptosis, defects in the pathway develop during malignant transformation, preventing apoptosis from occurring. How to specifically induce apoptosis in cancer cells remains unclear. Methods: We determined the apoptosome activity and p53 status of normal human cells and of lung, colon, stomach, brain, and breast cancer cells by measuring cytochrome c-dependent caspase activation and by DNA sequencing, respectively, and we used COMPARE analysis to identify apoptosome-specific agonists. We compared cell death, cytochrome c release, and caspase activation in NCI-H23 (lung cancer), HCT-15 (colon cancer), and SF268 (brain cancer) cells treated with Triacsin c, an inhibitor of acyl-CoA synthetase (ACS), or with vehicle. The cells were mock, transiently, or stably transfected with genes for Triacsin c-resistant ACSL5, dominant negative caspase-9, or apoptotic protease activating factor-1 knockdown. We measured ACS activity and levels of cardiolipin, a mitochondrial phospholipid, in mock and ACSL5-transduced SF268 cells. Nude mice carrying NCI-H23 xenograft tumors (n = 10) were treated with Triacsin c or vehicle, and xenograft tumor growth was assessed. Groups were compared using two-sided Student t tests. Results: Of 21 p53-defective tumor cell lines analyzed, 17 had higher apoptosome activity than did normal cells. Triacsin c selectively induced apoptosome-mediated death in tumor cells (caspase activity of Triacsin c-treated versus untreated SF268 cells; means = 1020% and 100%, respectively; difference = 920%, 95% CI = 900% to 940%; P<.001). Expression of ACSL5 suppressed Triacsin c-induced cytochrome c release and subsequent cell death (cell survival of Triacsin c-treated mock-versus ACSL5-transduced SF268 cells; means = 40% and 83%, respectively; difference = 43%, 95% CI = 39% to 47%; P<.001). ACS was also essential to the maintenance of cardiolipin levels. Finally, Triacsin c suppressed growth of xenograft tumors (relative tumor volume on day 21 of Triacsin c-treated versus untreated mice; means = 4.6 and 9.6, respectively; difference = 5.0, 95% CI = 2.1 to 7.9; P = .006). Conclusions: Many p53-defective tumors retain activity of the apoptosome, which is therefore a potential target for cancer chemotherapy. Inhibition of ACS may be a novel strategy to induce the death of p53-defective tumor cells.

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