Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins
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The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75 % (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50 % reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25 % compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.
KeywordsStatins Zoledronic acid Mevalonate pathway Dickkopf-1 Breast cancer Osteoblasts
The authors would like to thank Ms. Josefa Hötzel and Ms. Bärbel Zeiler for their excellent technical assistance and Ms. Theresa Reiche for her secretarial assistance. The work was funded by the Deutsche Forschungsgemeinschaft to Dr. Rachner (RA 2151/2-1 and 3-1) and to Dr. Hofbauer (HO 1875/15-1 and 16-1) as part of the DFG Research group SKELMET.
Study Design: AG and TDR. Study conduct: AG and AJB. Data collection: AG, AJB, and ST. Data analysis: AG, MR, ST and TDR. Data interpretation: AG, AJB, ST, MR, LCH, and TDR. Drafting Manuscript: AG and TDR. Revising manuscript content: AG, AJB, ST, MR, LCH, and TDR. Approving final version of manuscript: AG, AJB, ST, MR, LCH, and TDR. AG takes responsibility of the integrity of the data analysis.
Compliance with Ethical Standards
Conflict of Interest
The authors have received grants or honorarium for advisory boards or lectures to the individual or the institution by Amgen (LCH, TDR), Novartis (LCH, TDR), and Merck (LCH, TDR)). AG, AJB, ST, and MR declare no conflict of interest.
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