Cancer Biology Graduate Program, University of Arizona , Tucson, AZ, USA.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
J Cell Biol. 2023 Jun 5;222(6). doi: 10.1083/jcb.202208136. Epub 2023 Apr 12.
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.
区分促使惰性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迁移联系起来的新信号通路。一项无偏见的蛋白质组学筛选鉴定出 Abl 相互作用蛋白 2 (ABI2) 是波调节复合物 (WRC) 的一个组成部分，是 PIM1 的底物。PIM1 对 ABI2 的丝氨酸 183 进行磷酸化增加了 ABI2 蛋白水平，并增强了 WRC 的形成，从而增加了突起活性和细胞迁移。缺氧和/或 PIM1 诱导的细胞突起依赖于 ABI2。体内平滑肌侵袭实验表明，过表达 PIM1 显著增加了肿瘤细胞侵袭的深度，而 PIM 抑制剂的治疗显著降低了肌内 PCa 的侵袭。这项研究揭示了一条 HIF-1 非依赖性信号轴，对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剂的新作用。
