PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer.
PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer.
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卵巢癌中PBK通过TRIM 37/NFκB轴驱动PARP抑制剂耐药
DOI：
10.1038/s12276-022-00809-w
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发表时间：
2022-07
影响因子：
12.8
通讯作者：
Kong, Beihua
中科院分区：
文献类型：
--
作者：
Ma, Hanlin;Qi, Gonghua;Han, Fang;Peng, Jiali;Yuan, Cunzhong;Kong, Beihua
对PARP抑制剂（PARPi）的耐药性仍然是卵巢癌患者的治疗挑战。PDZ结合激酶（PBK）参与许多恶性肿瘤的化疗耐药性。然而，PI 3 K在卵巢癌PARPi耐药中的作用尚不清楚。在目前的研究中，我们证明了PI 3 K的过表达有助于卵巢癌细胞中奥拉帕尼耐药。PI 3 K的敲低使奥拉帕尼抗性SKOV 3细胞对奥拉帕尼敏感。使用特异性抑制剂抑制PI 3 K增强了奥拉帕尼的治疗效率。在机制上，PBK直接与TRIM 37相互作用，促进其磷酸化和核转位。随后激活NFκB通路。此外，PBK通过调节NFκB/TRIM 37轴增强卵巢癌对olaparib B的抵抗。综上所述，PI 3 K通过激活TRIM 37介导的NFκB通路而赋予卵巢癌对PARPi的耐药性，靶向抑制PI 3 K为改善卵巢癌患者PARPi治疗结局提供了新的治疗方法。一种与肿瘤进展有关的酶也有助于癌症挫败一种常用的靶向药物治疗。来自中国济南山东大学的Beihua Kong及其同事展示了PDZ结合激酶（PBK）是一种促进癌细胞增殖和扩散的酶，它如何激活一种信号通路，使肿瘤对奥拉帕尼治疗产生耐药性。这种精确的抗癌药物通过阻断一种名为PARP的蛋白质起作用，这种蛋白质通常帮助细胞修复受损的DNA。研究人员展示了PBK如何与另一种蛋白质相互作用，以刺激一种转录因子，这种转录因子以前被证明会降低放疗和化疗的有效性。阻断PI 3 K的活性，无论是通过基因或遗传途径，都能增强卵巢癌细胞对奥拉帕尼的敏感性。类似的药物策略可以帮助改善接受PARP抑制剂治疗的癌症患者的结果。
Resistance to PARP inhibitors (PARPi) remains a therapeutic challenge in ovarian cancer patients. PDZ-binding kinase (PBK) participates in the chemoresistance of many malignancies. However, the role of PBK in PARPi resistance of ovarian cancer is obscure. In the current study, we demonstrated that overexpression of PBK contributed to olaparib resistance in ovarian cancer cells. Knockdown of PBK sensitized olaparib-resistant SKOV3 cells to olaparib. Inhibition of PBK using a specific inhibitor enhanced the therapeutic efficiency of olaparib. Mechanically, PBK directly interacted with TRIM37 to promote its phosphorylation and nuclear translocation. which subsequently activates the NFκB pathway. Additionally, PBK enhanced olaparib resistance of ovarian cancer by regulating the NFκB/TRIM37 axis in vitro and in vivo. In conclusion, PBK confers ovarian cancer resistance to PARPi through activating the TRIM37-mediated NFκB pathway, and targeted inhibition of PBK provided the new therapy to improve PARPi treatment outcomes for ovarian cancer patients. An enzyme implicated in tumor progression also helps cancers thwart a commonly used type of targeted drug therapy. Beihua Kong and colleagues from Shandong University, Jinan, China, showed how PDZ-binding kinase (PBK), an enzyme that promotes the proliferation and spread of cancer cells, activates a signaling pathway that renders tumors resistant to treatment with olaparib. This precision anti-cancer drug works by blocking a protein called PARP that normally helps cells repair damaged DNA. The researchers showed how PBK interacts with another protein to stimulate a transcription factor previously shown to reduce the effectiveness of radiation and chemotherapy. Blocking the activity of PBK, either pharmacologically or genetically, enhanced the sensitivity of ovarian cancer cells to olaparib. A similar drug strategy could help improve outcomes for cancer patients undergoing PARP inhibitor treatment.
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