DDR1 (discoidin domain receptor tyrosine kinase 1) drives glioblastoma therapy resistance by modulating autophagy
DDR1 (discoidin domain receptor tyrosine kinase 1) drives glioblastoma therapy resistance by modulating autophagy
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DOI：
10.1080/15548627.2019.1618540
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发表时间：
2019-05-24
期刊：
影响因子：
13.3
通讯作者：
Cordes, Nils
中科院分区：
文献类型：
--
作者：
Vehlow, Anne;Cordes, Nils
肿瘤细胞的治疗抗性是有效抗癌治疗方法的主要障碍，并且已归因于肿瘤异质性以及遗传和表观遗传变化。越来越多的证据表明，肿瘤细胞粘附到细胞外基质作为一个额外的重要因素赋予肿瘤细胞抵抗放射性和化疗干预。我们最近的研究表明，DDR 1（discoidin domain receptor tyrosine kinase 1，盘状结构域受体酪氨酸激酶1）通过其粘附于细胞外基质和随后调节巨自噬/自噬来增强多形性胶质母细胞瘤（GBM）干细胞样和散装细胞的治疗抗性。在机制上，DDR 1与YWHA/14-3-3-BECN 1-AKT 1多蛋白复合物相关联，有利于促存活/抗自噬和抗性介导的AKT-MTOR信号传导。反过来，DDR 1的抑制通过诱导自噬使胶质母细胞瘤细胞对放疗和化疗敏感。总的来说，我们的研究表明，DDR 1可能是一个潜在的目标，敏感胶质母细胞瘤细胞的联合治疗，通过其有效诱导自噬细胞死亡。
Therapy resistance of tumor cells is a major obstacle for efficient anticancer treatment approaches and has been attributed to tumor heterogeneity as well as genetic and epigenetic changes. Accumulating evidence demonstrates that tumor cell adhesion to the extracellular matrix acts as an additional essential factor conferring tumor cell resistance to both radio- and chemotherapeutic intervention. Our recent study demonstrates that DDR1 (discoidin domain receptor tyrosine kinase 1) elicits therapy resistance of glioblastoma multiforme (GBM) stem-like and bulk cells through its adhesion to extracellular matrix and the subsequent modulation of macroautophagy/autophagy. Mechanistically, DDR1 associates with a YWHA/14-3-3-BECN1-AKT1 multiprotein complex favoring pro-survival/anti-autophagic and resistance-mediating AKT-MTOR signaling. In turn, inhibition of DDR1 sensitizes glioblastoma cells to radio- and chemotherapy by inducing autophagy. Collectively, our study suggests that DDR1 may be a potential target for sensitizing glioblastoma cells to combination therapies through its efficient induction of autophagic cell death.