Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Department of Pathology, University of Turku, Turku, Finland.
Cancer Res. 2016 Dec 1;76(23):7001-7011. doi: 10.1158/0008-5472.CAN-16-1134. Epub 2016 Sep 26.
Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here, we show that overexpression of the protein phosphatase 2A (PP2A) inhibitor protein PME-1 drives resistance of glioma cells to various multikinase inhibitors. The PME-1-elicited resistance was dependent on specific PP2A complexes and was mediated by a decrease in cytoplasmic HDAC4 activity. Importantly, both PME-1 and HDAC4 associated with human glioma progression, supporting clinical relevance of the identified mechanism. Synthetic lethality induced by both PME-1 and HDAC4 inhibition was dependent on the coexpression of proapoptotic protein BAD. Thus, PME-1-mediated PP2A inhibition is a novel mechanistic explanation for multikinase inhibitor resistance in glioma cells. Clinically, these results may inform patient stratification strategies for future clinical trials with selected kinase inhibitors in glioblastoma multiforme. Cancer Res; 76(23); 7001-11. ©2016 AACR.
多形性胶质母细胞瘤缺乏有效的治疗选择。虽然失调的激酶途径是多形性胶质母细胞瘤恶性进展的驱动因素，但神经胶质瘤细胞对许多激酶抑制剂表现出内在的耐药性，而这种耐药性的分子基础仍知之甚少。在这里，我们表明蛋白磷酸酶 2A（PP2A）抑制剂蛋白 PME-1 的过表达导致神经胶质瘤细胞对各种多激酶抑制剂的耐药性。PME-1 诱导的耐药性依赖于特定的 PP2A 复合物，并通过降低细胞质 HDAC4 活性来介导。重要的是，PME-1 和 HDAC4 均与人类胶质瘤的进展相关，支持所鉴定机制的临床相关性。由 PME-1 和 HDAC4 抑制诱导的合成致死性依赖于促凋亡蛋白 BAD 的共表达。因此，PME-1 介导的 PP2A 抑制是神经胶质瘤细胞对多激酶抑制剂耐药性的一种新的机制解释。临床上，这些结果可能为未来在多形性胶质母细胞瘤中选择激酶抑制剂的临床试验提供患者分层策略。癌症研究; 76(23); 7001-11。©2016 AACR.
