Abstract
Glioblastoma multiforme, the most common brain tumor, typically exhibits markedly increased angiogenesis, which is crucial for tumor growth and invasion. Antiangiogenic strategies based on disruption of the tumor microvasculature have proven effective for the treatment of experimental brain tumors. Here, we have overexpressed human caspase-9 by stable transfection in the SNB19 glioblastoma cell line, which normally expresses low levels of caspase-9. Our studies revealed that overexpression of caspase-9 coupled with radiation has a synergistic effect on the inhibition of glioma invasion as demonstrated by Matrigel assay (>65%). Furthermore, sense caspase stable clones cocultured with fetal rat brain aggregates along with radiation showed complete inhibition as compared to the parental and vector controls. During in vitro angiogenesis, SNB19 cells cocultured with human microvascular endothelial cells (HMEC) showed vascular network formation after 48-72 h. In contrast, these capillary-like structures were inhibited when HMEC cells were cocultured with sense caspase stable SNB19 cells. This effect was further enhanced by radiation (5Gy). Signaling mechanisms revealed that apoptosis is induced by cleavage of caspase-9 by radiation, loss of mitochondrial membrane potential and activation of caspase-3. These results demonstrate that activation of caspase-9 disrupts glioma cell invasion and angiogenesis in vitro. Hence, overexpression of proapoptotic molecules such as caspase-9 may be an important determinant of the therapeutic effect of radiation in cancer therapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2339-2346 |
| Number of pages | 8 |
| Journal | Oncogene |
| Volume | 23 |
| Issue number | 13 |
| DOIs | |
| State | Published - Mar 25 2004 |
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Keywords
- Caspase 9
- Glioma
- In version angiogenesis
- Radiation
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
Cite this
Activation of caspase-9 with irradiation inhibits invasion and angiogenesis in SNB19 human glioma cells. / Yanamandra, Niranjan; Kondraganti, Shakuntala; Srinivasula, Srinivasa M.; Gujrati, Meena; Olivero, William C.; Dinh, Dzung H.; Rao, Jasti S.
In: Oncogene, Vol. 23, No. 13, 25.03.2004, p. 2339-2346.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of caspase-9 with irradiation inhibits invasion and angiogenesis in SNB19 human glioma cells
AU - Yanamandra, Niranjan
AU - Kondraganti, Shakuntala
AU - Srinivasula, Srinivasa M.
AU - Gujrati, Meena
AU - Olivero, William C.
AU - Dinh, Dzung H.
AU - Rao, Jasti S.
PY - 2004/3/25
Y1 - 2004/3/25
N2 - Glioblastoma multiforme, the most common brain tumor, typically exhibits markedly increased angiogenesis, which is crucial for tumor growth and invasion. Antiangiogenic strategies based on disruption of the tumor microvasculature have proven effective for the treatment of experimental brain tumors. Here, we have overexpressed human caspase-9 by stable transfection in the SNB19 glioblastoma cell line, which normally expresses low levels of caspase-9. Our studies revealed that overexpression of caspase-9 coupled with radiation has a synergistic effect on the inhibition of glioma invasion as demonstrated by Matrigel assay (>65%). Furthermore, sense caspase stable clones cocultured with fetal rat brain aggregates along with radiation showed complete inhibition as compared to the parental and vector controls. During in vitro angiogenesis, SNB19 cells cocultured with human microvascular endothelial cells (HMEC) showed vascular network formation after 48-72 h. In contrast, these capillary-like structures were inhibited when HMEC cells were cocultured with sense caspase stable SNB19 cells. This effect was further enhanced by radiation (5Gy). Signaling mechanisms revealed that apoptosis is induced by cleavage of caspase-9 by radiation, loss of mitochondrial membrane potential and activation of caspase-3. These results demonstrate that activation of caspase-9 disrupts glioma cell invasion and angiogenesis in vitro. Hence, overexpression of proapoptotic molecules such as caspase-9 may be an important determinant of the therapeutic effect of radiation in cancer therapy.
AB - Glioblastoma multiforme, the most common brain tumor, typically exhibits markedly increased angiogenesis, which is crucial for tumor growth and invasion. Antiangiogenic strategies based on disruption of the tumor microvasculature have proven effective for the treatment of experimental brain tumors. Here, we have overexpressed human caspase-9 by stable transfection in the SNB19 glioblastoma cell line, which normally expresses low levels of caspase-9. Our studies revealed that overexpression of caspase-9 coupled with radiation has a synergistic effect on the inhibition of glioma invasion as demonstrated by Matrigel assay (>65%). Furthermore, sense caspase stable clones cocultured with fetal rat brain aggregates along with radiation showed complete inhibition as compared to the parental and vector controls. During in vitro angiogenesis, SNB19 cells cocultured with human microvascular endothelial cells (HMEC) showed vascular network formation after 48-72 h. In contrast, these capillary-like structures were inhibited when HMEC cells were cocultured with sense caspase stable SNB19 cells. This effect was further enhanced by radiation (5Gy). Signaling mechanisms revealed that apoptosis is induced by cleavage of caspase-9 by radiation, loss of mitochondrial membrane potential and activation of caspase-3. These results demonstrate that activation of caspase-9 disrupts glioma cell invasion and angiogenesis in vitro. Hence, overexpression of proapoptotic molecules such as caspase-9 may be an important determinant of the therapeutic effect of radiation in cancer therapy.
KW - Caspase 9
KW - Glioma
KW - In version angiogenesis
KW - Radiation
UR - http://www.scopus.com/inward/record.url?scp=1842432459&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1842432459&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1207406
DO - 10.1038/sj.onc.1207406
M3 - Article
C2 - 14767475
AN - SCOPUS:1842432459
VL - 23
SP - 2339
EP - 2346
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 13
ER -