TY - JOUR
T1 - NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction
AU - Kim, Ki Hyun
AU - Kim, Dongyoung
AU - Park, Ju Yeol
AU - Jung, Hye Jin
AU - Cho, Yong Hee
AU - Kim, Hyoung Kyu
AU - Han, Jin
AU - Choi, Kang Yell
AU - Kwon, Ho Jeong
N1 - Publisher Copyright:
© 2014, Springer-Verlag Berlin Heidelberg.
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Abstract: Mitochondrial respiration is required for hypoxia-inducible factor (HIF)-1α stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Herein, small molecules that inhibit HIF-1α protein stability by targeting mitochondrial energy production were screened using the Library of Pharmacologically Active Compounds and cell growth assay in galactose or glucose medium. NNC 55-0396, a T-type Ca2+ channel inhibitor, was selected as a hit from among 1,280 small molecules. NNC 55-0396 suppressed mitochondrial reactive oxygen species-mediated HIF-1α expression as well as stabilization by inhibiting protein synthesis in a dose-dependent manner. NNC 55-0396 inhibited tumor-induced angiogenesis in vitro and in vivo by suppressing HIF-1α stability. Moreover, NNC 55-0396 significantly suppressed glioblastoma tumor growth in a xenograft model. Thus, NNC 55-0396, a small molecule targeting T-type Ca2+ channel, was identified by the systemic cell-based assay and was shown to have antiangiogenic activity via the suppression of HIF-1α signal transduction. These results provide new insights into the biological network between ion channel and HIF-1α signal transduction. Key message: HIF-1α overexpression has been demonstrated in hypoxic cancer cells.NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibited HIF-1α expression via both proteasomal degradation and protein synthesis pathways.T-type Ca2+ channel inhibitors block angiogenesis by suppressing HIF-1α stability and synthesis.NNC 55-0396 could be a potential therapeutic drug candidate for cancer treatment.
AB - Abstract: Mitochondrial respiration is required for hypoxia-inducible factor (HIF)-1α stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Herein, small molecules that inhibit HIF-1α protein stability by targeting mitochondrial energy production were screened using the Library of Pharmacologically Active Compounds and cell growth assay in galactose or glucose medium. NNC 55-0396, a T-type Ca2+ channel inhibitor, was selected as a hit from among 1,280 small molecules. NNC 55-0396 suppressed mitochondrial reactive oxygen species-mediated HIF-1α expression as well as stabilization by inhibiting protein synthesis in a dose-dependent manner. NNC 55-0396 inhibited tumor-induced angiogenesis in vitro and in vivo by suppressing HIF-1α stability. Moreover, NNC 55-0396 significantly suppressed glioblastoma tumor growth in a xenograft model. Thus, NNC 55-0396, a small molecule targeting T-type Ca2+ channel, was identified by the systemic cell-based assay and was shown to have antiangiogenic activity via the suppression of HIF-1α signal transduction. These results provide new insights into the biological network between ion channel and HIF-1α signal transduction. Key message: HIF-1α overexpression has been demonstrated in hypoxic cancer cells.NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibited HIF-1α expression via both proteasomal degradation and protein synthesis pathways.T-type Ca2+ channel inhibitors block angiogenesis by suppressing HIF-1α stability and synthesis.NNC 55-0396 could be a potential therapeutic drug candidate for cancer treatment.
UR - http://www.scopus.com/inward/record.url?scp=84937524196&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937524196&partnerID=8YFLogxK
U2 - 10.1007/s00109-014-1235-1
DO - 10.1007/s00109-014-1235-1
M3 - Article
C2 - 25471482
AN - SCOPUS:84937524196
VL - 93
SP - 499
EP - 509
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 5
ER -