HOXA5-Induced Apoptosis in Breast Cancer Cells Is Mediated by Caspases 2 and 8

Hexin Chen, Seung Chung, Saraswati Sukumar

Research output: Contribution to journalArticle

Abstract

HOXA5 is a transcriptional factor whose expression is lost in more than 60% of breast carcinomas. Our previous work demonstrated that the overexpression of HOXA5 in MCF7 cells resulted in cell death through a p53-dependent apoptotic pathway. To determine whether p53-independent apoptotic pathways are involved in HOXA5-induced cell death, we engineered a p53-mutant breast cancer cell line, Hs578T, to inducibly express HOXA5. Induction of HOXA5 expression led to cell death with features typical of apoptosis within 24 h, and the expression levels of mutant p53 and its target genes either decreased or remained unchanged. To decipher apoptotic pathways, the HOXA5-expressing cells were treated with a variety of apoptotic inhibitors. Besides a general caspase inhibitor, caspase 2- and 8-specific inhibitors largely abolished HOXA5-induced apoptosis, whereas caspase 1-, 3-, 6-, and 9-specific inhibitors had no significant effects. Western blot analysis further confirmed that caspases 2 and 8 were activated after the induction of HOXA5 expression. Further, several small interfering RNAs which specifically silenced caspase 2 and caspase 8 expression significantly blocked HOXA5-induced apoptosis. HOXA5 expression could also sensitize cells to tumor necrosis factor alpha-induced apoptosis by at least 100-fold. These results indicate that expression of HOXA5 can induce apoptosis through an apoptotic mechanism mediated by caspases 2 and 8.

Original languageEnglish (US)
Pages (from-to)924-935
Number of pages12
JournalMolecular and Cellular Biology
Volume24
Issue number2
DOIs
StatePublished - Jan 2004

Fingerprint

Caspase 2
Caspase 8
Apoptosis
Breast Neoplasms
Cell Death
Far-Western Blotting
Caspase 1
Caspase Inhibitors
MCF-7 Cells
Caspase 3
Small Interfering RNA
Tumor Necrosis Factor-alpha
Cell Line
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

HOXA5-Induced Apoptosis in Breast Cancer Cells Is Mediated by Caspases 2 and 8. / Chen, Hexin; Chung, Seung; Sukumar, Saraswati.

In: Molecular and Cellular Biology, Vol. 24, No. 2, 01.2004, p. 924-935.

Research output: Contribution to journalArticle

@article{b3deb3f6ed2649f1acd28af78f641e47,
title = "HOXA5-Induced Apoptosis in Breast Cancer Cells Is Mediated by Caspases 2 and 8",
abstract = "HOXA5 is a transcriptional factor whose expression is lost in more than 60{\%} of breast carcinomas. Our previous work demonstrated that the overexpression of HOXA5 in MCF7 cells resulted in cell death through a p53-dependent apoptotic pathway. To determine whether p53-independent apoptotic pathways are involved in HOXA5-induced cell death, we engineered a p53-mutant breast cancer cell line, Hs578T, to inducibly express HOXA5. Induction of HOXA5 expression led to cell death with features typical of apoptosis within 24 h, and the expression levels of mutant p53 and its target genes either decreased or remained unchanged. To decipher apoptotic pathways, the HOXA5-expressing cells were treated with a variety of apoptotic inhibitors. Besides a general caspase inhibitor, caspase 2- and 8-specific inhibitors largely abolished HOXA5-induced apoptosis, whereas caspase 1-, 3-, 6-, and 9-specific inhibitors had no significant effects. Western blot analysis further confirmed that caspases 2 and 8 were activated after the induction of HOXA5 expression. Further, several small interfering RNAs which specifically silenced caspase 2 and caspase 8 expression significantly blocked HOXA5-induced apoptosis. HOXA5 expression could also sensitize cells to tumor necrosis factor alpha-induced apoptosis by at least 100-fold. These results indicate that expression of HOXA5 can induce apoptosis through an apoptotic mechanism mediated by caspases 2 and 8.",
author = "Hexin Chen and Seung Chung and Saraswati Sukumar",
year = "2004",
month = "1",
doi = "10.1128/MCB.24.2.924-935.2004",
language = "English (US)",
volume = "24",
pages = "924--935",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "2",

}

TY - JOUR

T1 - HOXA5-Induced Apoptosis in Breast Cancer Cells Is Mediated by Caspases 2 and 8

AU - Chen, Hexin

AU - Chung, Seung

AU - Sukumar, Saraswati

PY - 2004/1

Y1 - 2004/1

N2 - HOXA5 is a transcriptional factor whose expression is lost in more than 60% of breast carcinomas. Our previous work demonstrated that the overexpression of HOXA5 in MCF7 cells resulted in cell death through a p53-dependent apoptotic pathway. To determine whether p53-independent apoptotic pathways are involved in HOXA5-induced cell death, we engineered a p53-mutant breast cancer cell line, Hs578T, to inducibly express HOXA5. Induction of HOXA5 expression led to cell death with features typical of apoptosis within 24 h, and the expression levels of mutant p53 and its target genes either decreased or remained unchanged. To decipher apoptotic pathways, the HOXA5-expressing cells were treated with a variety of apoptotic inhibitors. Besides a general caspase inhibitor, caspase 2- and 8-specific inhibitors largely abolished HOXA5-induced apoptosis, whereas caspase 1-, 3-, 6-, and 9-specific inhibitors had no significant effects. Western blot analysis further confirmed that caspases 2 and 8 were activated after the induction of HOXA5 expression. Further, several small interfering RNAs which specifically silenced caspase 2 and caspase 8 expression significantly blocked HOXA5-induced apoptosis. HOXA5 expression could also sensitize cells to tumor necrosis factor alpha-induced apoptosis by at least 100-fold. These results indicate that expression of HOXA5 can induce apoptosis through an apoptotic mechanism mediated by caspases 2 and 8.

AB - HOXA5 is a transcriptional factor whose expression is lost in more than 60% of breast carcinomas. Our previous work demonstrated that the overexpression of HOXA5 in MCF7 cells resulted in cell death through a p53-dependent apoptotic pathway. To determine whether p53-independent apoptotic pathways are involved in HOXA5-induced cell death, we engineered a p53-mutant breast cancer cell line, Hs578T, to inducibly express HOXA5. Induction of HOXA5 expression led to cell death with features typical of apoptosis within 24 h, and the expression levels of mutant p53 and its target genes either decreased or remained unchanged. To decipher apoptotic pathways, the HOXA5-expressing cells were treated with a variety of apoptotic inhibitors. Besides a general caspase inhibitor, caspase 2- and 8-specific inhibitors largely abolished HOXA5-induced apoptosis, whereas caspase 1-, 3-, 6-, and 9-specific inhibitors had no significant effects. Western blot analysis further confirmed that caspases 2 and 8 were activated after the induction of HOXA5 expression. Further, several small interfering RNAs which specifically silenced caspase 2 and caspase 8 expression significantly blocked HOXA5-induced apoptosis. HOXA5 expression could also sensitize cells to tumor necrosis factor alpha-induced apoptosis by at least 100-fold. These results indicate that expression of HOXA5 can induce apoptosis through an apoptotic mechanism mediated by caspases 2 and 8.

UR - http://www.scopus.com/inward/record.url?scp=0347986652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0347986652&partnerID=8YFLogxK

U2 - 10.1128/MCB.24.2.924-935.2004

DO - 10.1128/MCB.24.2.924-935.2004

M3 - Article

VL - 24

SP - 924

EP - 935

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 2

ER -