Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.
Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Nat Commun. 2018 Feb 2;9(1):476. doi: 10.1038/s41467-017-02811-7.
Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.
虽然紫杉醇被广泛应用于癌症治疗，但它仅能在一小部分患者中引发反应。紫杉醇对肿瘤的反应强烈取决于微管动态不稳定性的状态。然而，是否可以通过操纵这一生理过程来增强紫杉醇的反应尚未得到验证。在这里，我们展示了微管相关蛋白 CRMP2 的一个先前未被认识的作用，即通过其羧基末端诱导微管的束集。当 FER 酪氨酸激酶在 Y479 和 Y499 处使 CRMP2 磷酸化时，这种活性显著降低。野生型 CRMP2 和 CRMP2-Y479E 的晶体结构揭示了模拟磷酸化如何防止 CRMP2 的四聚化。用亚治疗剂量的抑制剂耗尽 FER 或降低其催化活性可增加卵巢癌细胞和体内紫杉醇诱导的微管稳定性和细胞毒性。这项工作为抑制 FER 介导的 CRMP2 磷酸化以增强紫杉醇的靶向活性用于癌症治疗提供了依据。
