Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells.
Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells.
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DOI：
10.1038/cddis.2013.165
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发表时间：
2013-05-23
影响因子：
9
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含氮二磷酸盐(N-BP)唑来膦酸(ZOL)抑制破骨细胞介导的骨吸收，用于预防骨转移引起的骨骼并发症。ZOL还在临床前模型和最近的癌症患者中展示了抗癌活性，突显了人们对确定对这种药物的最终耐药机制的兴趣。在我们的研究中，我们选择了前列腺癌(PCA)细胞的耐药亚系并对其进行了表征，以更好地了解肿瘤细胞逃避ZOL抗肿瘤作用的机制。用递增浓度的ZOL从DU145亲本细胞中筛选出DU145R80抗性细胞，用大约5个月的时间。DU145R80细胞的耐药指数为5.5，对另一种N-BP-帕米磷酸酯有交叉耐药性，但对非含氮BP氯膦酸盐无交叉耐药性。值得注意的是，与DU145亲本细胞相比，DU145R80表现出对凋亡和失巢凋亡的抵抗，并过度表达抗凋亡蛋白Bcl-2和癌蛋白c-Myc。此外，DU145R80细胞经历了上皮向间充质转化(EMT)，表现出金属蛋白酶MMP2/9表达增加，侵袭能力增强。有趣的是，与DU145相比，DU145R80细胞还增加了血管内皮生长因子和细胞因子嗜酸性粒细胞趋化因子-1和白介素12的基因表达和蛋白分泌。在分子水平上，与亲代敏感细胞相比，DU145R80细胞表现出强烈的p38-MAPK依赖的生存通路的激活。此外，使用p38-抑制剂SB203580，我们完全逆转了对ZOL的抗性，以及EMT标记的表达和侵袭。此外，SB203580还降低了血管内皮生长因子、嗜酸性粒细胞趋化因子-1、IL-12、基质金属蛋白酶-9、Bcl-2和c-Myc的表达。因此，我们首次证明了p38-MAPK通路可以在持续广泛暴露于ZOL的情况下在前列腺癌细胞中被激活，并且p38-MAPK通路在诱导抗性以及获得更具侵袭性和侵袭性的表型中具有关键作用。
The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.
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