Journal of the National Cancer Institute Advance Access originally published online on January 27, 2009
JNCI Journal of the National Cancer Institute 2009 101(3):176-193; doi:10.1093/jnci/djn470
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© The Author 2009. Published by Oxford University Press.
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The Role of STAT-3 in the Induction of Apoptosis in Pancreatic Cancer Cells by Benzyl Isothiocyanate
Affiliation of authors: Department of Pharmaceutical Sciences and Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX (RPS, SKS)
Correspondence to: Sanjay K. Srivastava, PhD, Department of Pharmaceutical Sciences and Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Suite 404, 1300 S Coulter, Amarillo, TX 79106 (e-mail: sanjay.srivastava{at}ttuhsc.edu).
Background: Benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, has been reported to have anticancer properties, but the mechanism whereby it inhibits growth of human pancreatic cancer cells is incompletely understood.
Methods: Human pancreatic cancer cells (BxPC-3, AsPC-1, Capan-2, MiaPaCa-2, and Panc-1) and immortalized human pancreatic cells (HPDE-6) were treated with vehicle or with BITC at 5–40 µM, cell survival was evaluated by sulforhodamine B assay, and apoptosis by caspase-3 and poly-ADP ribose polymerase cleavage or by a commercial assay for cell death. Total and activated signal transducer and activator of transcription-3 (STAT-3) protein expression in the cells were examined by western blotting, STAT-3 mRNA levels by reverse transcription–polymerase chain reaction, and STAT-3 DNA-binding and transcriptional activity by commercially available binding and reporter assays. The effects of BITC treatment on tumor growth, apoptosis, and STAT-3 protein expression in vivo were studied in xenografts of BxPC-3 pancreatic tumor cells in athymic nude mice. All statistical tests were two-sided.
Results: BITC treatment reduced cell survival and induced apoptosis in BxPC-3, AsPC-1, Capan-2, and MiaPaCa-2 cells, and to a much lesser extent in Panc-1 cells, but not in HPDE-6 cells. It also reduced levels of activated and total STAT-3 protein, and as a result, STAT-3 DNA-binding and transcriptional activities. Overexpression of STAT-3 in BxPC-3 cells inhibited BITC-induced apoptosis and restored STAT-3 activity. In mice that were fed BITC (60 µmol/wk, five mice, 10 tumors per group), growth of BxPC-3 pancreatic tumor xenografts was suppressed compared with control mice (at 6 weeks, mean tumor volume of control vs BITC-treated mice = 334 vs 172 mm3, difference =162 mm3, 95% confidence interval = 118 to 204 mm3; P = .008) and tumors had increased apoptosis and reduced STAT-3 protein expression.
Conclusion: BITC induces apoptosis in some types of pancreatic cancer cells by inhibiting the STAT-3 signaling pathway.
| CONTEXT AND CAVEATS Prior knowledge Benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, has been reported to have anticancer properties. The mechanism by which it inhibits proliferation of human pancreatic cancer cells in culture was not well understood. Study design Human pancreatic cancer cell lines and a human nonmalignant, but immortalized, pancreatic cell line were used to examine the effects of BITC on proliferation and survival and on STAT-3 expression and activity in vitro. A mouse model of pancreatic cancer was used to study the effects of BITC on tumor growth in vivo. Contribution BITC treatment increased cell death in the pancreatic cancer cell lines tested compared with the nonmalignant cell line. BITC-sensitive cells also showed reduced levels of total and activated STAT-3 protein. Overexpression of STAT-3 eliminated BITC-induced apoptosis. Tumors grew more slowly in mice fed BITC than in untreated control mice. Implications BITC induces apoptosis by a STAT-3–dependent mechanism in several human pancreatic cancer cell lines. Limitations BITC promoted cell death and inhibited STAT-3 activation to varying degrees in several pancreatic cancer cell lines. Only one nonmalignant pancreatic cell line was studied. The in vivo experiments were performed in a small number of mice that were continuously fed BITC from the time of tumor cell implantation, and it is not clear whether the protective dose would be practical in terms of human consumption of vegetables. From the Editors
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Manuscript received January 28, 2008; revised October 17, 2008; accepted November 19, 2008.
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J Natl Cancer Inst 2009 101: 127.
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  A. B. Hanley and R. Burch Re: The Role of STAT-3 in the Induction of Apoptosis in Pancreatic Cancer Cells by Benzyl Isothiocyanate J Natl Cancer Inst, June 16, 2009; 101(12): 893 - 893. [Full Text] [PDF]
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S. K. Srivastava and R. P. Sahu Response: Re: The Role of STAT-3 in the Induction of Apoptosis in Pancreatic Cancer Cells by Benzyl Isothiocyanate J Natl Cancer Inst, June 16, 2009; 101(12): 893 - 894. [Full Text] [PDF]
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