Distinguishing key factors that drive the switch from indolent to invasive disease will make a significant impact on guiding the treatment of prostate cancer (PCa) patients. Here, we identify a novel signaling pathway linking hypoxia and PIM1 kinase to the actin cytoskeleton and cell motility. An unbiased proteomic screen identified Abl-interactor 2 (ABI2), an integral member of the wave regulatory complex (WRC), as a PIM1 substrate. Phosphorylation of ABI2 at Ser183 by PIM1 increased ABI2 protein levels and enhanced WRC formation, resulting in increased protrusive activity and cell motility. Cell protrusion induced by hypoxia and/or PIM1 was dependent on ABI2. In vivo smooth muscle invasion assays showed that overexpression of PIM1 significantly increased the depth of tumor cell invasion, and treatment with PIM inhibitors significantly reduced intramuscular PCa invasion. This research uncovers a HIF-1-independent signaling axis that is critical for hypoxia-induced invasion and establishes a novel role for PIM1 as a key regulator of the actin cytoskeleton.

中文翻译：

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PIM1 磷酸化 ABI2 以增强肌动蛋白动力学并促进肿瘤侵袭

区分推动惰性疾病向侵袭性疾病转变的关键因素将对指导前列腺癌（PCa）患者的治疗产生重大影响。在这里，我们确定了一条将缺氧和 PIM1 激酶与肌动蛋白细胞骨架和细胞运动联系起来的新信号通路。无偏见的蛋白质组学筛选将波调节复合体 (WRC) 的组成部分 Abl-相互作用蛋白 2 (ABI2) 鉴定为 PIM1 底物。 PIM1 对 ABI2 Ser183 的磷酸化增加了 ABI2 蛋白水平并增强了 WRC 形成，从而导致突出活性和细胞运动性增加。缺氧和/或 PIM1 诱导的细胞突出依赖于 ABI2。体内平滑肌侵袭实验表明，PIM1的过度表达显着增加了肿瘤细胞侵袭的深度，并且PIM抑制剂的治疗显着减少了肌内PCa侵袭。这项研究揭示了一个独立于 HIF-1 的信号轴，该轴对于缺氧诱导的侵袭至关重要，并确立了 PIM1 作为肌动蛋白细胞骨架关键调节因子的新作用。