Department of Radiotherapy and Radiooncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Cell Stress Chaperones. 2013 Mar;18(2):183-91. doi: 10.1007/s12192-012-0369-8. Epub 2012 Aug 30.
The oncoprotein MDM2 (murine double minute 2) is often overexpressed in human tumors and thereby attenuates the function of the tumor suppressor p53. In this study, we investigated the effects of the novel MDM2-inhibitor PXN727 on p53 activation, cell proliferation, cell cycle distribution and radiosensitivity. Since the localization of heat shock protein 70 (Hsp70) exerts different effects on radioresistance of tumor cells, we investigated the impact of PXN727 on intracellular, membrane, and secreted Hsp70 levels. We could show that PXN727 exerts its effects on wildtype p53 (HCT116 p53⁺/⁺, A549) but not p53 depleted (HCT116 p53⁻/⁻) or mutated (FaDu) tumor cells. PXN727 activates p53, induces the expression of p21, reduces the proportion of cells in the radioresistant S-phase and induces senescence. Radiosensitivity was significantly increased by PXN727 in HCT116 p53⁺/⁺ tumor cells. Furthermore, PXN727 causes a downregulation of Hsp70 membrane expression and an upregulated secretion of Hsp70 in wildtype p53 tumor cells. Our data suggest that re-activation of p53 by MDM2-inhibition modulates Hsp70 membrane expression and secretion which might contribute to the radiosensitizing effect of the MDM2-inhibitor PXN727.
癌蛋白 MDM2（鼠双微体 2）在人类肿瘤中常过度表达，从而削弱肿瘤抑制因子 p53 的功能。在这项研究中，我们研究了新型 MDM2 抑制剂 PXN727 对 p53 激活、细胞增殖、细胞周期分布和放射敏感性的影响。由于热休克蛋白 70（Hsp70）的定位对肿瘤细胞的放射抵抗有不同的影响，我们研究了 PXN727 对细胞内、膜和分泌型 Hsp70 水平的影响。我们可以证明 PXN727 对野生型 p53（HCT116 p53⁺/⁺，A549）发挥作用，但对 p53 缺失（HCT116 p53⁻/⁻）或突变（FaDu）的肿瘤细胞没有作用。PXN727 激活 p53，诱导 p21 的表达，减少放射抵抗 S 期细胞的比例，并诱导衰老。PXN727 显著增加 HCT116 p53⁺/⁺ 肿瘤细胞的放射敏感性。此外，PXN727 导致野生型 p53 肿瘤细胞中 Hsp70 膜表达下调和 Hsp70 分泌上调。我们的数据表明，MDM2 抑制重新激活 p53 可调节 Hsp70 膜表达和分泌，这可能有助于 MDM2 抑制剂 PXN727 的放射增敏作用。
