Tang X, Zhang Q, Shi S, Yun Y, Li X, Zhang Y, Zhou K, Le AD
Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells. [JOURNAL ARTICLE]
Int J Cancer 2009 Jun 30.
Adjunctive chemotherapy with bisphosphonates has been reported to delay bone metastasis and improve overall survival in breast cancer. Aside from its anti-resorptive effect, bisphosphonates exhibit antitumor activities, in vitro and in vivo, via several mechanisms including anti-angiogenesis. In this study, we investigated the potential molecular mechanisms underlying the anti-angiogenic effect of non nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, in IGF-1 responsive human breast cancer cells. We tested whether bisphosphonates had any effects on HIF-1alpha/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 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 PI-3K/AKT/mTOR 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. (c) 2009 UICC.
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