Shanghai Key Laboratory of Compound Chinese Medicines, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 201620, China.
Cancer Lett. 2022 Oct 1;545:215829. doi: 10.1016/j.canlet.2022.215829. Epub 2022 Jul 19.
Acquired docetaxel (doc) resistance, one of the major reasons for unfavorable prognosis in patients with aggressive hormone-independent prostate cancer (HIPC), is a major obstacle for patient treatment. Dysregulation of long non-coding RNAs promotes or suppresses chemoresistance in multiple cancers; however, the specific molecular mechanisms underlying HIPC remain unknown. In this study, we found that the LINC01085, as a tumor-suppressor, which showed significant clinically relevant in HIPC patients with doc-resistance. Mechanistically, in docetaxel-sensitive cells, LINC01085 could specifically bind to both TANK-binding kinase 1 (TBK1) and glycogen synthase kinase 3β (GSK3β), and higher LINC01085 RNA levels could inhibit TBK1 dimerization. Whereas, in doc-resistant cells, lower LINC01085 RNA level lost the strong binding with both, meanwhile, the interaction between TBK1 and GSK3β enhanced which accelerated TBK1 phosphorylation at the Ser-172 site, resulting in decreased expression levels of PD-L1 and NF-κB as well as the secretion of type I/III interferons. Thus, Overexpression of LINC01085 combined with immune checkpoint blockade is an effective strategy for the treatment of HIPC patients.
获得性多西紫杉醇（doc）耐药性是侵袭性非激素依赖性前列腺癌（HIPC）患者预后不良的主要原因之一，也是患者治疗的主要障碍。长链非编码 RNA 的失调促进或抑制了多种癌症的化疗耐药性；然而，HIPC 的确切分子机制尚不清楚。在这项研究中，我们发现 LINC01085 作为一种肿瘤抑制因子，在具有 doc 耐药性的 HIPC 患者中具有显著的临床相关性。在机制上，在多西紫杉醇敏感的细胞中，LINC01085 可以特异性地与 TANK 结合激酶 1（TBK1）和糖原合酶激酶 3β（GSK3β）结合，并且更高的 LINC01085 RNA 水平可以抑制 TBK1 二聚化。然而，在 doc 耐药的细胞中，较低的 LINC01085 RNA 水平失去了与两者的强结合，同时，TBK1 和 GSK3β 之间的相互作用增强，加速了 TBK1 在 Ser-172 位点的磷酸化，导致 PD-L1 和 NF-κB 的表达水平降低以及 I/III 型干扰素的分泌减少。因此，LINC01085 的过表达与免疫检查点阻断相结合是治疗 HIPC 患者的有效策略。
