Santio Niina M, Salmela Maria, Arola Heidi, Eerola Sini K, Heino Jyrki, Rainio Eeva-Marja, Koskinen Päivi J
Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland; Drug Research Doctoral Programme, University of Turku, 20520 Turku, Finland.
Department of Biochemistry, University of Turku, 20500 Turku, Finland.
Exp Cell Res. 2016 Mar 15;342(2):113-24. doi: 10.1016/j.yexcr.2016.02.018. Epub 2016 Mar 2.
The ability of cells to migrate and form metastases is one of the fatal hallmarks of cancer that can be conquered only with better understanding of the molecules and regulatory mechanisms involved. The oncogenic PIM kinases have been shown to support cancer cell survival and motility, but the PIM-regulated pathways stimulating cell migration and invasion are less well characterized than those affecting cell survival. Here we have identified the glycogen synthase kinase 3β (GSK3B) and the forkhead box P3 (FOXP3) transcription factor as direct PIM targets, whose tumour-suppressive effects in prostate cancer cells are inhibited by PIM-induced phosphorylation, resulting in increased cell migration. Targeting GSK3B is also essential for the observed PIM-enhanced expression of the prostaglandin-endoperoxide synthase 2 (PTGS2), which is an important regulator of both cell migration and adhesion. Accordingly, selective inhibition of PIM activity not only reduces cell migration, but also affects integrin-mediated cell adhesion. Taken together, these data provide novel mechanistic insights on how and why patients with metastatic prostate cancer may benefit from therapies targeting PIM kinases, and how such approaches may also be applicable to inflammatory conditions.
细胞迁移和形成转移灶的能力是癌症致命的特征之一，只有更好地了解其中涉及的分子和调控机制才能攻克这一难题。致癌性PIM激酶已被证明可支持癌细胞的存活和运动，但与影响细胞存活的途径相比，PIM调节的刺激细胞迁移和侵袭的途径的特征尚不明确。在这里，我们确定糖原合酶激酶3β（GSK3B）和叉头框P3（FOXP3）转录因子是PIM的直接靶点，PIM诱导的磷酸化抑制了它们在前列腺癌细胞中的肿瘤抑制作用，导致细胞迁移增加。靶向GSK3B对于观察到的PIM增强的前列腺素内过氧化物合酶2（PTGS2）的表达也至关重要，PTGS2是细胞迁移和黏附的重要调节因子。因此，选择性抑制PIM活性不仅会减少细胞迁移，还会影响整合素介导的细胞黏附。综上所述，这些数据为转移性前列腺癌患者如何以及为何可能从靶向PIM激酶的治疗中获益，以及这些方法如何也适用于炎症性疾病提供了新的机制见解。
