Rodriguez-Cupello Carmen, Dam Monica, Serini Laura, Wang Shan, Lindgren David, Englund Emelie, Kjellman Pontus, Axelson Håkan, García-Mariscal Alberto, Madsen Chris D
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Front Cell Dev Biol. 2020 Mar 17;8:146. doi: 10.3389/fcell.2020.00146. eCollection 2020.
The STRIPAK complex has been linked to a variety of biological processes taking place during embryogenesis and development, but its role in cancer has only just started to be defined. Here, we expand on previous work indicating a role for the scaffolding protein STRIP1 in cancer cell migration and metastasis. We show that cell cycle arrest and decreased proliferation are seen upon loss of STRIP1 in MDA-MB-231 cells due to the induction of cyclin dependent kinase inhibitors, including p21 and p27. We demonstrate that p21 and p27 induction is observed in a subpopulation of cells having low DNA damage response and that the p21/γH2AX ratio within single cells can be rescued by depleting MST3&4 kinases. While the loss of STRIP1 decreases cell proliferation and tumor growth, cells treated with low dosage of chemotherapeutics paradoxically escape therapy-induced senescence and begin to proliferate after recovery. This corroborates with already known research on the dual role of p21 and indicates that STRIP1 also plays a contradictory role in breast cancer, suppressing tumor growth, but once treated with chemotherapeutics, allowing for possible recurrence and decreased patient survival.
STRIPAK复合物与胚胎发生和发育过程中发生的多种生物学过程相关，但它在癌症中的作用才刚刚开始被明确。在这里，我们扩展了先前的研究工作，表明支架蛋白STRIP1在癌细胞迁移和转移中发挥作用。我们发现，MDA-MB-231细胞中STRIP1缺失时，由于细胞周期蛋白依赖性激酶抑制剂（包括p21和p27）的诱导，会出现细胞周期停滞和增殖减少的情况。我们证明，在DNA损伤反应较低的细胞亚群中观察到p21和p27的诱导，并且通过消耗MST3和4激酶可以挽救单细胞内的p21/γH2AX比率。虽然STRIP1的缺失会降低细胞增殖和肿瘤生长，但用低剂量化疗药物处理的细胞却反常地逃避了治疗诱导的衰老，并在恢复后开始增殖。这与已知的关于p21双重作用的研究结果相佐证，表明STRIP1在乳腺癌中也发挥着矛盾的作用，抑制肿瘤生长，但一旦接受化疗，可能会导致复发并降低患者生存率。
