Abstract
The mitochondrial antioxidant enzyme manganese-containing superoxide dismutase (MnSOD) functions as a tumor suppressor gene. Reconstitution of MnSOD expression in several human cancer cell lines leads to reversion of malignancy and induces a resistant phenotype to the cytotoxic effects of TNF and hyperthermia. The signaling pathways that underlie these phenotypic changes in MnSOD-overexpressing cells are unknown, although alterations in the activity of several redox-sensitive transcription factors, including AP-1 and NF-κB, have been observed. To determine the downstream signaling molecules involved in MnSOD-induced cell resistant phenotype, in the present study we analyzed the expression profile of several groups of genes related to stress response, DNA repair, and apoptosis, in a human breast cancer MCF-7 cell line overexpressing MnSOD (MCF+SOD). Of 588 genes examined, 5 (0.85%) were up-regulated (2-42-fold), and 11 (1.9%) were down-regulated (2-33-fold) in the MCF+SOD cells compared to the parental MCF-7 cells. The five up-regulated genes were MET, GADD153, CD9, α-catenin and plakoglobin. The genes with the most significant down-regulation included: vascular endothelial growth factor receptor 1, TNF-α converting enzyme, and interleukin-1β. GADD153 (involved in the repair of DNA double strand breaks) showed a 33-fold increase in microarray analysis and these results were confirmed by RT-PCR. To further determine the specificity in MnSOD-induced gene regulation, MCF+SOD cells were stably transfected with an antisense MnSOD sequence whose expression was controlled by a tetracycline-inducible regulator. Expression of three up-regulated genes was measured after induction of antisense MnSOD expression. Interestingly, expression level of GADD153 but not MET or CD9 was reduced 24 h after antisense MnSOD induction. Together, these results suggest that reconstitution of MnSOD in tumor cells can specifically modulate the expression of down-stream effector genes. GADD153 and other elements observed in the MCF+SOD cells may play a key role in signaling the MnSOD-induced cell phenotypic change.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 260-267 |
| Number of pages | 8 |
| Journal | Free Radical Biology and Medicine |
| Volume | 30 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 1 2001 |
| Externally published | Yes |
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Keywords
- DNA microarray
- Free radicals
- GADD153
- Human breast cancer
- MnSOD
ASJC Scopus subject areas
- Medicine(all)
- Toxicology
- Clinical Biochemistry
Cite this
Genes regulated in human breast cancer cells overexpressing manganese-containing superoxide dismutase. / Li, Zhongkui; Khaletskiy, Alexander; Wang, Jianyi; Wong, Jeffrey Y C; Oberley, Larry W.; Li, Jian-Jian.
In: Free Radical Biology and Medicine, Vol. 30, No. 3, 01.02.2001, p. 260-267.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genes regulated in human breast cancer cells overexpressing manganese-containing superoxide dismutase
AU - Li, Zhongkui
AU - Khaletskiy, Alexander
AU - Wang, Jianyi
AU - Wong, Jeffrey Y C
AU - Oberley, Larry W.
AU - Li, Jian-Jian
PY - 2001/2/1
Y1 - 2001/2/1
N2 - The mitochondrial antioxidant enzyme manganese-containing superoxide dismutase (MnSOD) functions as a tumor suppressor gene. Reconstitution of MnSOD expression in several human cancer cell lines leads to reversion of malignancy and induces a resistant phenotype to the cytotoxic effects of TNF and hyperthermia. The signaling pathways that underlie these phenotypic changes in MnSOD-overexpressing cells are unknown, although alterations in the activity of several redox-sensitive transcription factors, including AP-1 and NF-κB, have been observed. To determine the downstream signaling molecules involved in MnSOD-induced cell resistant phenotype, in the present study we analyzed the expression profile of several groups of genes related to stress response, DNA repair, and apoptosis, in a human breast cancer MCF-7 cell line overexpressing MnSOD (MCF+SOD). Of 588 genes examined, 5 (0.85%) were up-regulated (2-42-fold), and 11 (1.9%) were down-regulated (2-33-fold) in the MCF+SOD cells compared to the parental MCF-7 cells. The five up-regulated genes were MET, GADD153, CD9, α-catenin and plakoglobin. The genes with the most significant down-regulation included: vascular endothelial growth factor receptor 1, TNF-α converting enzyme, and interleukin-1β. GADD153 (involved in the repair of DNA double strand breaks) showed a 33-fold increase in microarray analysis and these results were confirmed by RT-PCR. To further determine the specificity in MnSOD-induced gene regulation, MCF+SOD cells were stably transfected with an antisense MnSOD sequence whose expression was controlled by a tetracycline-inducible regulator. Expression of three up-regulated genes was measured after induction of antisense MnSOD expression. Interestingly, expression level of GADD153 but not MET or CD9 was reduced 24 h after antisense MnSOD induction. Together, these results suggest that reconstitution of MnSOD in tumor cells can specifically modulate the expression of down-stream effector genes. GADD153 and other elements observed in the MCF+SOD cells may play a key role in signaling the MnSOD-induced cell phenotypic change.
AB - The mitochondrial antioxidant enzyme manganese-containing superoxide dismutase (MnSOD) functions as a tumor suppressor gene. Reconstitution of MnSOD expression in several human cancer cell lines leads to reversion of malignancy and induces a resistant phenotype to the cytotoxic effects of TNF and hyperthermia. The signaling pathways that underlie these phenotypic changes in MnSOD-overexpressing cells are unknown, although alterations in the activity of several redox-sensitive transcription factors, including AP-1 and NF-κB, have been observed. To determine the downstream signaling molecules involved in MnSOD-induced cell resistant phenotype, in the present study we analyzed the expression profile of several groups of genes related to stress response, DNA repair, and apoptosis, in a human breast cancer MCF-7 cell line overexpressing MnSOD (MCF+SOD). Of 588 genes examined, 5 (0.85%) were up-regulated (2-42-fold), and 11 (1.9%) were down-regulated (2-33-fold) in the MCF+SOD cells compared to the parental MCF-7 cells. The five up-regulated genes were MET, GADD153, CD9, α-catenin and plakoglobin. The genes with the most significant down-regulation included: vascular endothelial growth factor receptor 1, TNF-α converting enzyme, and interleukin-1β. GADD153 (involved in the repair of DNA double strand breaks) showed a 33-fold increase in microarray analysis and these results were confirmed by RT-PCR. To further determine the specificity in MnSOD-induced gene regulation, MCF+SOD cells were stably transfected with an antisense MnSOD sequence whose expression was controlled by a tetracycline-inducible regulator. Expression of three up-regulated genes was measured after induction of antisense MnSOD expression. Interestingly, expression level of GADD153 but not MET or CD9 was reduced 24 h after antisense MnSOD induction. Together, these results suggest that reconstitution of MnSOD in tumor cells can specifically modulate the expression of down-stream effector genes. GADD153 and other elements observed in the MCF+SOD cells may play a key role in signaling the MnSOD-induced cell phenotypic change.
KW - DNA microarray
KW - Free radicals
KW - GADD153
KW - Human breast cancer
KW - MnSOD
UR - http://www.scopus.com/inward/record.url?scp=0035254175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035254175&partnerID=8YFLogxK
U2 - 10.1016/S0891-5849(00)00468-8
DO - 10.1016/S0891-5849(00)00468-8
M3 - Article
C2 - 11165872
AN - SCOPUS:0035254175
VL - 30
SP - 260
EP - 267
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 3
ER -