CDK4/6 抑制通过 RB 的核转位启动细胞周期停滞,并诱发多步分子反应。

IF 6.1 2区 生物学 Q1 CELL BIOLOGY
Ting Hong, Anna C Hogger, Dongbiao Wang, Qi Pan, Julie Gansel, Thomas Engleitner, Rupert Öllinger, Jürgen E Gschwend, Roland Rad, Roman Nawroth
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引用次数: 0

摘要

CDK4/6 抑制剂是治疗转移性乳腺癌的标准药物。由于在大多数临床试验中,CDK4/6抑制剂作为单一疗法的疗效相当有限,因此治疗方案包括与内分泌疗法联合使用。因此,了解治疗反应的分子机制可能有助于改进治疗设计。我们利用 RNA 测序分析了膀胱癌细胞在 48 小时内对 CDK4/6 抑制剂 palbociclib 的反应,并确定了反应的多步骤机制。接下来,我们将这些结果转化为膀胱癌细胞在PD治疗后的分子机制。第一步的特点是通过激活导入蛋白α/β将 RB 蛋白转位到细胞核中,这一机制需要 NLS 序列。与此同时,RB 在细胞质中被蛋白水解,这一过程受 gankyrin 和 SCF 复合物的调控。只有低磷酸化的 RB 才会在细胞核中积聚,而这是通过启动 G1 停顿实现高效治疗反应的必要步骤。这可能是 RB 阴性或突变患者反应不佳的原因。在治疗的后期阶段,MiT/TFE 蛋白家族表达的增加会导致溶酶体生物生成,这对维持这种反应至关重要。最后,CDK4/6抑制后,癌细胞要么衰老和凋亡,要么产生抗药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CDK4/6 inhibition initiates cell cycle arrest by nuclear translocation of RB and induces a multistep molecular response.

CDK4/6 inhibitors are standard of care in the treatment of metastatic breast cancer. Treatment regimen consists of a combination with endocrine therapy, since their therapeutic efficacy as monotherapy in most clinical trials was rather limited. Thus, understanding the molecular mechanisms that underlie response to therapy might allow for the development of an improved therapy design. We analyzed the response to the CDK4/6 inhibitor palbociclib in bladder cancer cells over a 48-hour time course using RNA sequencing and identified a multi-step mechanism of response. We next translated these results to the molecular mechanism in bladder cancer cells upon PD treatment. The initial step is characterized by translocation of the RB protein into the nucleus by activation of importin α/β, a mechanism that requires the NLS sequence. In parallel, RB is proteolyzed in the cytoplasm, a process regulated by gankyrin and the SCF complex. Only hypophosphorylated RB accumulates in the nucleus, which is an essential step for an efficient therapy response by initiating G1 arrest. This might explain the poor response in RB negative or mutated patients. At later stages during therapy, increased expression of the MiT/TFE protein family leads to lysosomal biogenesis which is essential to maintain this response. Lastly, cancer cells either undergo senescence and apoptosis or develop mechanisms of resistance following CDK4/6 inhibition.

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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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