TY - JOUR
T1 - Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis
AU - Lee, Seon Jin
AU - Kim, Hong Pyo
AU - Jin, Yang
AU - Choi, Augustine M.K.
AU - Ryter, Stefan W.
N1 - Funding Information:
Cruz, sc-108062) for 2 hconfluent. The media was %. 10 nchangPM siRNed to traOA wansfectPs incuion mUbated wedia (Eith Santa JTR01-Hwas sUL0uppS799ortJ04 aed Cndby NV a FIH grUAMantFRI Clinical Innovator Award s R01-HL60234, R01-HL55330, transfection reagent (Santa Cruz, sc-108061) for 1 h and then to A.M.K. Choi. S. Ryter was supported by NIH grants added to each well. After 4–6 h, the media was aspirated and (R01-HL60234, R01-HL079904) and received salary support complete media replaced in each well. from the Lovelace Respiratory Research Institute.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2011/8
Y1 - 2011/8
N2 - Beclin 1, a tumor suppressor protein, acts as an initiator of autophagy in mammals. Heterozygous disruption of Beclin 1 accelerates tumor growth, but the underlying mechanisms remain unclear. We examined the role of Beclin 1 in tumor proliferation and angiogenesis, using a primary mouse melanoma tumor model. Beclin 1 (Becn1+/-) hemizygous mice displayed an aggressive tumor growth phenotype with increased angiogenesis under hypoxia, associated with enhanced levels of circulating erythropoietin but not vascular endothelial growth factor, relative to wild-type mice. Using in vivo and ex vivo assays, we demonstrated increased angiogenic activity in Becn1+/- mice relative to wild-type mice. Endothelial cells from Becn1+/- mice displayed increased proliferation, migration and tube formation in response to hypoxia relative to wild-type cells. Moreover, Becn1+/- cells subjected to hypoxia displayed increased hypoxia-inducible factor-2α (HIF-2α) expression relative to HIF-1α. Genetic interference of HIF-2α but not HIF-1α, dramatically reduced hypoxia-inducible proliferation, migration and tube formation in Becn1+/- endothelial cells. We demonstrated that mice deficient in the autophagic protein Beclin 1 display a pro-angiogenic phenotype associated with the upregulation of HIF- 2α and increased erythropoietin production. These results suggest a relationship between Beclin 1 and the regulation of angiogenesis, with implications in tumor growth and development.
AB - Beclin 1, a tumor suppressor protein, acts as an initiator of autophagy in mammals. Heterozygous disruption of Beclin 1 accelerates tumor growth, but the underlying mechanisms remain unclear. We examined the role of Beclin 1 in tumor proliferation and angiogenesis, using a primary mouse melanoma tumor model. Beclin 1 (Becn1+/-) hemizygous mice displayed an aggressive tumor growth phenotype with increased angiogenesis under hypoxia, associated with enhanced levels of circulating erythropoietin but not vascular endothelial growth factor, relative to wild-type mice. Using in vivo and ex vivo assays, we demonstrated increased angiogenic activity in Becn1+/- mice relative to wild-type mice. Endothelial cells from Becn1+/- mice displayed increased proliferation, migration and tube formation in response to hypoxia relative to wild-type cells. Moreover, Becn1+/- cells subjected to hypoxia displayed increased hypoxia-inducible factor-2α (HIF-2α) expression relative to HIF-1α. Genetic interference of HIF-2α but not HIF-1α, dramatically reduced hypoxia-inducible proliferation, migration and tube formation in Becn1+/- endothelial cells. We demonstrated that mice deficient in the autophagic protein Beclin 1 display a pro-angiogenic phenotype associated with the upregulation of HIF- 2α and increased erythropoietin production. These results suggest a relationship between Beclin 1 and the regulation of angiogenesis, with implications in tumor growth and development.
KW - Angiogenesis
KW - Autophagy
KW - Beclin 1
KW - Hypoxia-inducible factor
UR - http://www.scopus.com/inward/record.url?scp=79961102995&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79961102995&partnerID=8YFLogxK
U2 - 10.4161/auto.7.8.15598
DO - 10.4161/auto.7.8.15598
M3 - Article
C2 - 21685724
AN - SCOPUS:79961102995
VL - 7
SP - 829
EP - 839
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 8
ER -