Inhibition of angiogenesis by quercetin in tamoxifen-resistant breast cancer cells.
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem among breast cancer patients. Previously, we have reported that TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) showed increased angiogenic intensity through Pin1-dependent vascular endothelial growth factor (VEGF) production. Among six flavonoids tested in the current study, VEGF gene transcription in MCF-7 cells with stable Pin1 overexpression was inhibited most effectively by quercetin. Reporter gene assays using minimal reporters containing hypoxia response elements and activator protein-1 (AP-1) elements revealed that the activities of hypoxia inducible factor-1α (HIF-1α) and AP-1, key transcription factors for VEGF gene transcription, were suppressed by quercetin. Western blot analyses confirmed that the increased nuclear levels of c-Jun and HIF-1α in TAMR-MCF-7 cells were blocked by quercetin. Moreover, quercetin inhibited the enhanced VEGF secretion and Pin1 expression in TAMR-MCF-7 cells, which was dependent on its phosphatidyl inositol 3-kinase inhibiting effect. Chick chorioallantoic membrane assays demonstrated that the enhanced angiogenesis intensity of TAMR-MCF-7 cells was also suppressed significantly by quercetin. These results demonstrate that quercetin may have therapeutic potential for the treatment of TAM-resistant breast cancer via Pin1 inhibition.
Oh
Soo Jin
SJ
College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Kim
Ok
O
Lee
Jong Suk
JS
Kim
Jung-Ae
JA
Kim
Mi Ra
MR
Choi
Hong Seok
HS
Shim
Jeong-Hyun
JH
Kang
Keon Wook
KW
Kim
Young Chul
YC
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D000975:Antioxidants; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D011794:Quercetin; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase