BLU enhances the effects of anti-angiogenic activity in combination with gemcitabine-based chemotherapeutic agents

Heon Jong Yoo, Boh Ram Kim, Hyun Jung Byun, Sang Yoon Park, Seung Bae Rho

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

BLU is a tumor suppressor protein that is down-regulated in ovarian and cervical cancers. Its cellular biological functions appear related to cancer inhibition. We presently demonstrate that BLU has direct anti-tumor and anti-angiogenic effects on ovarian carcinoma and human umbilical vein endothelial cells in vitro by the arrest of the cell cycle and induction of apoptosis. BLU in combination with gemcitabine arrested the cell cycle at the G1-G0 phase and induced apoptosis. BLU actively contributed to cell growth by enhancing gemcitabine-inhibited cell migration and tubule formation in angiogenesis and tumorigenesis. The combined treatment with BLU and gemcitabine further activated p53 and p21 expression, whereas the productions of Bcl-2, Bcl-xL, and nuclear factor-kappa B proteins were decreased, with BLU possibly being more effective in the treatment of ovarian cancer when given in combination with gemcitabine, rather than as a single agent. Furthermore, as expected, BLU plus gemcitabine significantly inhibited the phosphorylation of signaling modulators downstream of phosphoinositide 3-kinase, such as phospho-phosphoinositide-dependent protein kinase 1, Akt, and mammalian target of rapamycin, as well as hypoxia-inducible factor-1α and vascular endothelial growth factor. Taken together, our results provide evidence that BLU can effectively regulate the pro-apoptotic and anti-angiogenic activity of gemcitabine through the direct interaction with vascular endothelial growth factor receptor-2, as well as the up-regulation of p21 and p53 expression.

Original languageEnglish
Pages (from-to)1236-1245
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume45
Issue number7
DOIs
StatePublished - 9 May 2013

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gemcitabine
Phosphatidylinositols
Ovarian Neoplasms
Cells
Apoptosis
Tumor Suppressor Proteins
Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor Receptor-2
Cell Cycle Resting Phase
Phosphorylation
1-Phosphatidylinositol 4-Kinase
NF-kappa B
Endothelial cells
Human Umbilical Vein Endothelial Cells
G1 Phase
Cell growth
Sirolimus
Cell Cycle Checkpoints
Uterine Cervical Neoplasms
Protein Kinases

Keywords

  • Angiogenesis
  • Cell cycle arrest
  • Gemcitabine traditional chemotherapeutic agent
  • Tumor suppressor BLU gene
  • Tumorigenesis
  • VEGF receptor-2

Cite this

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title = "BLU enhances the effects of anti-angiogenic activity in combination with gemcitabine-based chemotherapeutic agents",
abstract = "BLU is a tumor suppressor protein that is down-regulated in ovarian and cervical cancers. Its cellular biological functions appear related to cancer inhibition. We presently demonstrate that BLU has direct anti-tumor and anti-angiogenic effects on ovarian carcinoma and human umbilical vein endothelial cells in vitro by the arrest of the cell cycle and induction of apoptosis. BLU in combination with gemcitabine arrested the cell cycle at the G1-G0 phase and induced apoptosis. BLU actively contributed to cell growth by enhancing gemcitabine-inhibited cell migration and tubule formation in angiogenesis and tumorigenesis. The combined treatment with BLU and gemcitabine further activated p53 and p21 expression, whereas the productions of Bcl-2, Bcl-xL, and nuclear factor-kappa B proteins were decreased, with BLU possibly being more effective in the treatment of ovarian cancer when given in combination with gemcitabine, rather than as a single agent. Furthermore, as expected, BLU plus gemcitabine significantly inhibited the phosphorylation of signaling modulators downstream of phosphoinositide 3-kinase, such as phospho-phosphoinositide-dependent protein kinase 1, Akt, and mammalian target of rapamycin, as well as hypoxia-inducible factor-1α and vascular endothelial growth factor. Taken together, our results provide evidence that BLU can effectively regulate the pro-apoptotic and anti-angiogenic activity of gemcitabine through the direct interaction with vascular endothelial growth factor receptor-2, as well as the up-regulation of p21 and p53 expression.",
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BLU enhances the effects of anti-angiogenic activity in combination with gemcitabine-based chemotherapeutic agents. / Yoo, Heon Jong; Kim, Boh Ram; Byun, Hyun Jung; Park, Sang Yoon; Rho, Seung Bae.

In: International Journal of Biochemistry and Cell Biology, Vol. 45, No. 7, 09.05.2013, p. 1236-1245.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - BLU enhances the effects of anti-angiogenic activity in combination with gemcitabine-based chemotherapeutic agents

AU - Yoo, Heon Jong

AU - Kim, Boh Ram

AU - Byun, Hyun Jung

AU - Park, Sang Yoon

AU - Rho, Seung Bae

PY - 2013/5/9

Y1 - 2013/5/9

N2 - BLU is a tumor suppressor protein that is down-regulated in ovarian and cervical cancers. Its cellular biological functions appear related to cancer inhibition. We presently demonstrate that BLU has direct anti-tumor and anti-angiogenic effects on ovarian carcinoma and human umbilical vein endothelial cells in vitro by the arrest of the cell cycle and induction of apoptosis. BLU in combination with gemcitabine arrested the cell cycle at the G1-G0 phase and induced apoptosis. BLU actively contributed to cell growth by enhancing gemcitabine-inhibited cell migration and tubule formation in angiogenesis and tumorigenesis. The combined treatment with BLU and gemcitabine further activated p53 and p21 expression, whereas the productions of Bcl-2, Bcl-xL, and nuclear factor-kappa B proteins were decreased, with BLU possibly being more effective in the treatment of ovarian cancer when given in combination with gemcitabine, rather than as a single agent. Furthermore, as expected, BLU plus gemcitabine significantly inhibited the phosphorylation of signaling modulators downstream of phosphoinositide 3-kinase, such as phospho-phosphoinositide-dependent protein kinase 1, Akt, and mammalian target of rapamycin, as well as hypoxia-inducible factor-1α and vascular endothelial growth factor. Taken together, our results provide evidence that BLU can effectively regulate the pro-apoptotic and anti-angiogenic activity of gemcitabine through the direct interaction with vascular endothelial growth factor receptor-2, as well as the up-regulation of p21 and p53 expression.

AB - BLU is a tumor suppressor protein that is down-regulated in ovarian and cervical cancers. Its cellular biological functions appear related to cancer inhibition. We presently demonstrate that BLU has direct anti-tumor and anti-angiogenic effects on ovarian carcinoma and human umbilical vein endothelial cells in vitro by the arrest of the cell cycle and induction of apoptosis. BLU in combination with gemcitabine arrested the cell cycle at the G1-G0 phase and induced apoptosis. BLU actively contributed to cell growth by enhancing gemcitabine-inhibited cell migration and tubule formation in angiogenesis and tumorigenesis. The combined treatment with BLU and gemcitabine further activated p53 and p21 expression, whereas the productions of Bcl-2, Bcl-xL, and nuclear factor-kappa B proteins were decreased, with BLU possibly being more effective in the treatment of ovarian cancer when given in combination with gemcitabine, rather than as a single agent. Furthermore, as expected, BLU plus gemcitabine significantly inhibited the phosphorylation of signaling modulators downstream of phosphoinositide 3-kinase, such as phospho-phosphoinositide-dependent protein kinase 1, Akt, and mammalian target of rapamycin, as well as hypoxia-inducible factor-1α and vascular endothelial growth factor. Taken together, our results provide evidence that BLU can effectively regulate the pro-apoptotic and anti-angiogenic activity of gemcitabine through the direct interaction with vascular endothelial growth factor receptor-2, as well as the up-regulation of p21 and p53 expression.

KW - Angiogenesis

KW - Cell cycle arrest

KW - Gemcitabine traditional chemotherapeutic agent

KW - Tumor suppressor BLU gene

KW - Tumorigenesis

KW - VEGF receptor-2

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U2 - 10.1016/j.biocel.2013.04.001

DO - 10.1016/j.biocel.2013.04.001

M3 - Article

VL - 45

SP - 1236

EP - 1245

JO - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

SN - 1357-2725

IS - 7

ER -