Göbel Andy, Browne Andrew J, Thiele Stefanie, Rauner Martina, Hofbauer Lorenz C, Rachner Tilman D
Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
Breast Cancer Res Treat. 2015 Dec;154(3):623-31. doi: 10.1007/s10549-015-3624-8. Epub 2015 Oct 29.
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.
Wnt 抑制剂 Dickkopf-1（DKK-1）通过直接抑制成骨细胞分化和间接激活破骨细胞来促进癌症诱导的溶骨性骨病变。DKK-1 在人乳腺癌细胞中高表达，并且可被甲羟戊酸途径抑制剂如他汀类药物和氨基双膦酸盐所抑制。然而，需要超生理浓度才能抑制 DKK-1。我们发现，与单独使用单一药物相比，序贯使用他汀类药物和氨基双膦酸盐阻断甲羟戊酸途径能更显著地抑制 DKK-1。因此，唑来膦酸与低浓度他汀类药物（阿托伐他汀、辛伐他汀和瑞舒伐他汀）联合使用时，可使人类亲骨性肿瘤细胞系 MDA-MB-231、MDA-MET 和 MDA-BONE 中 DKK-1 的表达和分泌降低多达 75%（p < 0.05）。使用法尼基焦磷酸或香叶基香叶基焦磷酸对异戊二烯化进行特异性挽救表明，这些作用是由香叶基香叶基化受抑制介导的，而非法尼基化受抑制。此外，低浓度他汀类药物（1 μM 阿托伐他汀或 0.25 μM 辛伐他汀）与低浓度唑来膦酸联合使用，可使乳腺癌来源的 DKK-1 介导的 C2C12 细胞中成骨标志物抑制作用至少逆转 50%（p < 0.05）。最后，在皮下 MDA-MB-231 小鼠模型中瘤内注射阿托伐他汀和唑来膦酸，与未治疗的小鼠相比，可使人类 DKK-1 的血清水平降低 25%。因此，我们的研究表明，序贯阻断甲羟戊酸途径允许联合使用低浓度的他汀类药物和氨基双膦酸盐。这种联合用药仍能显著抑制乳腺癌来源的 DKK-1，使其降至不再能抑制 Wnt 介导的成骨细胞分化的水平。
