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PMID: 19569175 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells.

International journal of cancer ·Vol. 126 ·No. 1 ·2010-01-01 ·Pages 90-103

Tang X, Zhang Q, Shi S, Yen Y, Li X, Zhang Y, Zhou K, Le AD

Abstract

Adjunctive chemotherapy with bisphosphonates has been reported to delay bone metastasis and improve overall survival in breast cancer. Aside from its antiresorptive effect, bisphosphonates exhibit antitumor activities, in vitro and in vivo, via several mechanisms, including antiangiogenesis. In this study, we investigated the potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells. We tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1alpha/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis, and our results showed that both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1alpha protein accumulation and VEGF expression in MCF-7 cells. Mechanistically, we found that either pamidronate or clodronate did not affect mRNA expression of HIF-1alpha, but they apparently promoted the degradation of IGF-1-induced HIF-1alpha protein. Meanwhile, we found that the presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1alpha protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting the inhibition of protein synthesis. In addition, our results indicated that the inhibitory effects of bisphosphonates on the HIF-1alpha/VEGF axis are associated with the inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways. Consistently, we demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in the inhibition of tumor angiogenesis in breast cancer cells.

MeSH Terms
Base Sequence Breast Neoplasms/blood supply,metabolism,pathology Cell Line, Tumor DNA Primers Diphosphonates/pharmacology Enzyme-Linked Immunosorbent Assay Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Immunohistochemistry Insulin-Like Growth Factor I/physiology Neovascularization, Pathologic/prevention & control Phosphatidylinositol 3-Kinases/metabolism Protein Kinases/metabolism Proto-Oncogene Proteins c-akt/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/physiology TOR Serine-Threonine Kinases Vascular Endothelial Growth Factor A/metabolism
Chemicals
DNA Primers Diphosphonates HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Vascular Endothelial Growth Factor A Insulin-Like Growth Factor I Protein Kinases MTOR protein, human Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tang Xudong
Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, CA 90033, USA.
Zhang Qunzhou
Shi Shihong
Yen Yun
Li Xiangyong
Zhang Yuefei
Zhou Keyuan
Le Anh D
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Article Info
Journal
International journal of cancer
Abbr.
Int J Cancer
ISSN
1097-0215
DOI
10.1002/ijc.24710
Published
2010-01-01
Pages
90-103
Language
English
Region
United States
NLM ID
0042124
PMCID
PMC2784023
Subset
IM
Grants
NIAMS NIH HHS · S11 AR047359 · United States
NCI NIH HHS · R03 CA128099 · United States
NIAMS NIH HHS · 1S11 AR47359 · United States
NCI NIH HHS · R03 CA128099-02 · United States
NIDCR NIH HHS · R01 DE019932 · United States
External Links
PubMed source DOI: 10.1002/ijc.24710 PMC Full Text View journal details
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