The role of MAPK 38 in resistance of breast cancer and osteolytic bone metastases to inhibitors of the mevalonate pathway

MAPK 38 在乳腺癌和溶骨性骨转移对甲羟戊酸途径抑制剂抵抗中的作用

• 批准号: 215688817
• 负责人: Professor Dr. Lorenz C. Hofbauer
• 金额: --
• 依托单位: Bereich Endokrinologie, Diabetes und Knochenstoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/215688817?language=en
• 关键词: role; MAPK; 38; resistance; breast

The mevalonate pathway is an essential signaling pathway that can be blocked by bisphosphonates and statins. While bisphosphonates inhibit bone-resorbing osteoclasts, statins are used to lower the synthesis of cholesterol. Numerous studies describe direct and indirect anti-tumor effects by both drugs. However, high concentrations, which likely exceed those attainable in clinical practice, are required to obtain significant effects. In the first funding period, we demonstrated that sequential blockade of the mevalonate pathway using statins and zoledronic acid significantly lowers the concentrations of these drugs needed to achieve effective anti-tumor effects in human breast cancer cells. In addition, a significant suppression of DKK-1 was observed using this approach. DKK-1 is an inhibitor of osteoblastic differentiation and has emerged as a key modulator of osteolytic bone metastases. However, the treatment with statins and zoledronic acid activated the mitogen activated protein kinase (MAPK) p38, and pharmacological inhibition of p38 enhanced the induction of apoptosis by atorvastatin in breast cancer cells. Furthermore, a direct regulation of DKK-1 by p38 was demonstrated in human cancer cells.Based on these findings we hypothesize that activation of p38 results in a breast cancer cell resistance to the anti-tumor activities of mevalonate pathway inhibitors. Thus, we consider the blockade of p38 as a promising approach to sensitize human breast cancer cells to the anti-tumor and DKK-1 suppressive effects of statins and zoledronic acid. To test this hypothesis, we first aim to comprehensively characterize the anti-tumor effects mediated by the simultaneous inhibition of p38 and the mevalonate pathway. Specifically, we intend to identify the respective isoforms of p38 that are responsible for the observed resistance. Our findings will be confirmed by using appropriate animal models of both primary tumor growth and osteolytic bone metastases. Here, p38 will be knocked down using RNA interference or pharmacological inhibitors in the tumor cells, and mice will be treated with statins and zoledronic acid after tumor cell inoculation. Thus, we will assess if and how the reduced expression of DKK-1 in the tumor cells might potentially reduce the occurrence of osteolytic lesions in bone metastases. To underline the significance of our findings, primary breast cancer tissue will be analyzed to determine a link between the mevalonate pathway activity with the expression of DKK-1 and p38. Our study aims to identify an important resistance mechanism of breast cancer cells against inhibitors of the mevalonate pathway that might contribute to ineffective anti-tumor effects observed with clinical doses of statins and zoledronic acid.

甲伐他汀途径是一条重要的信号通路，可被双膦酸类和他汀类药物阻断。虽然双膦酸盐抑制破骨细胞的吸收，但他汀类药物用于降低胆固醇的合成。大量研究描述了这两种药物的直接和间接抗肿瘤作用。然而，要获得显著的效果，就需要很高的浓度，很可能超过临床实践中所能达到的浓度。在第一个资助期，我们证明了使用他汀类药物和唑来膦酸顺序阻断甲伐他汀类药物通路，显著降低了这些药物在人乳腺癌细胞中实现有效抗肿瘤效果所需的浓度。此外，使用该方法还观察到对DKK-1的显著抑制。DKK-1是成骨细胞分化的抑制因子，是溶骨性骨转移的关键调节因子。然而，他汀类药物和唑来膦酸处理激活了丝裂原活化蛋白激酶(MAPK)p38，药物抑制p38增强了阿托伐他汀诱导乳腺癌细胞凋亡的作用。此外，在人类癌细胞中发现了p38对DKK-1的直接调节作用。根据这些发现，我们推测p38的激活导致乳腺癌细胞对甲氧戊酸途径抑制剂的抗肿瘤活性产生抵抗。因此，我们认为阻断p38是一种有希望的方法来增强人乳腺癌细胞对他汀类药物和唑来膦酸的抗肿瘤和DKK-1抑制作用。为了验证这一假设，我们首先旨在全面表征同时抑制p38和甲羟戊酸途径所介导的抗肿瘤作用。具体地说，我们打算确定与所观察到的耐药性有关的p38的各个亚型。我们的发现将通过使用适当的原发肿瘤生长和溶骨性骨转移的动物模型来证实。在这里，p38将通过RNA干扰或药物抑制剂在肿瘤细胞中被击倒，小鼠将在肿瘤细胞接种后接受他汀类药物和唑来膦酸的治疗。因此，我们将评估DKK-1在肿瘤细胞中的表达降低是否以及如何潜在地减少骨转移瘤中溶骨性病变的发生。为了强调我们的发现的重要性，我们将分析原发乳腺癌组织，以确定甲氧戊酸途径活性与DKK-1和p38表达之间的联系。我们的研究旨在确定乳腺癌细胞对甲氧戊酸途径抑制剂的一个重要耐药机制，这可能是他汀类药物和唑来膦酸临床剂量观察到的无效抗肿瘤作用的原因之一。