Department of Biological Sciences, Pusan National University, Busandaehak-ro 63, Geumjeong-gu, Busan, 609-735, South Korea.
Pharmacol Res. 2013 Apr;70(1):90-101. doi: 10.1016/j.phrs.2013.01.005. Epub 2013 Jan 23.
Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC). However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC. To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases. Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells. Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC. After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were selected as candidates of PIM1 inhibitors that act as radiosensitizers. With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization. When PIM1 kinase activity was suppressed by these inhibitors, PRAS40 was not phosphorylated. Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a. Nuclear FOXO3a promoted the expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells. Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors. In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone. Taken together, our findings provided evidence that PIM1-specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance.
放疗在非小细胞肺癌（NSCLC）的治疗中起着关键作用。然而，放射抵抗是提高 NSCLC 放疗效率的主要障碍。为了了解 NSCLC 放射抵抗的机制，我们之前专注于 PIM1、PRAS40、FOXO3a、14-3-3 和蛋白磷酸酶的潜在参与。在这些蛋白质中，PIM1 作为癌基因发挥作用，并且被发现是放射抵抗 NSCLC 细胞中的关键介质。因此，我们研究了使用 PIM1 特异性抑制剂作为调节 NSCLC 放射敏感性的新型治疗药物。经过基于结构的药物选择，SGI-1776、ETP-45299 和色胺酮被选为作用于放射增敏剂的 PIM1 抑制剂候选物。在照射下，这些药物仅抑制 PIM1 激酶活性，而不影响 PIM1 mRNA/蛋白水平或细胞定位。当这些抑制剂抑制 PIM1 激酶活性时，PRAS40 不被磷酸化。因此，未磷酸化的 PRAS40 不会与 14-3-3 和 FOXO3a 形成三聚体复合物，导致 FOXO3a 核定位增加。核 FOXO3a 促进促凋亡蛋白如 Bim 和 FasL 的表达，从而对放射抵抗的 NSCLC 细胞产生放射增敏作用。此外，体内异种移植小鼠模型证实了 PIM1 抑制剂诱导的这种放射增敏作用。在这些模型系统中，与单独照射相比，联合照射和 PIM1 抑制剂治疗可显著减少肿瘤体积。总之，我们的研究结果提供了证据，表明 PIM1 特异性抑制剂 SGI-1776、ETP-45299 和色胺酮可以作为新型放射增敏剂，通过抑制与放射抵抗相关的照射诱导信号通路来增强放疗的疗效。
