Chk1 targeting reactivates PP2A tumor suppressor activity in cancer cells.
Chk1 targeting reactivates PP2A tumor suppressor activity in cancer cells.
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DOI：
10.1158/0008-5472.can-13-1002
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发表时间：
2013-11-15
期刊：
影响因子：
11.2
通讯作者：
Westermarck J
中科院分区：
文献类型：
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作者：
Khanna A;Kauko O;Böckelman C;Laine A;Schreck I;Partanen JI;Szwajda A;Bormann S;Bilgen T;Helenius M;Pokharel YR;Pimanda J;Russel MR;Haglund C;Cole KA;Klefström J;Aittokallio T;Weiss C;Ristimäki A;Visakorpi T;Westermarck J
检查点激酶Chk 1在许多癌细胞类型中具有组成性活性，新一代Chk 1抑制剂作为单一药物显示出显著的抗肿瘤活性。在这里，我们提出了一个迄今未被认识的机制，有助于癌细胞对Chk 1靶向治疗的反应。抑制癌细胞中的慢性Chk 1活性诱导蛋白磷酸酶PP 2A的肿瘤抑制活性，其通过使MYC丝氨酸62去磷酸化来抑制MYC活性并损害癌细胞存活。机制研究表明，Chk 1抑制激活PP 2A通过减少CIP 2A的转录，PP 2A活性的主要抑制剂。通过Chk 1抑制对癌细胞克隆形成的抑制可以在体外通过外源性表达CIP 2A或通过阻断CIP 2A调节的PP 2A复合物来挽救。Chk 1介导的CIP 2A调节在依赖于Chk 1或CIP 2A的肿瘤模型中延长。CIP 2A作为Chk 1效应蛋白的临床相关性在几种人类癌症类型中得到验证，包括神经母细胞瘤，其中CIP 2A被鉴定为NMYC独立的预后因子。由于Chk 1-CIP 2A-PP 2A通路是由DNA-PK活性驱动的，无论p53或ATM/ATR状态如何，我们的研究结果为理解Chk 1抑制剂如何介导单药抗癌功效提供了解释力。此外，他们将癌细胞中的CIP 2A-PP 2A状态定义为它们对Chk 1靶向治疗的反应的药效学标志物。
Checkpoint kinase Chk1 is constitutively active in many cancer cell types and new generation Chk1 inhibitors show marked antitumor activity as single agents. Here we present a hitherto unrecognized mechanism that contributes to the response of cancer cells to Chk1 targeted therapy. Inhibiting chronic Chk1 activity in cancer cells induced the tumor suppressor activity of protein phosphatase PP2A, which by dephosphorylating MYC serine 62, inhibited MYC activity and impaired cancer cell survival. Mechanistic investigations revealed that Chk1 inhibition activated PP2A by decreasing the transcription of CIP2A, a chief inhibitor of PP2A activity. Inhibition of cancer cell clonogenicity by Chk1 inhibition could be rescued in vitro either by exogenous expression of CIP2A or by blocking the CIP2A-regulated PP2A complex. Chk1-mediated CIP2A regulation was extended in tumor models dependent on either Chk1 or CIP2A. The clinical relevance of CIP2A as a Chk1 effector protein was validated in several human cancer types, including neuroblastoma where CIP2A was identified as a NMYC-independent prognostic factor. Since the Chk1-CIP2A-PP2A pathway is driven by DNA-PK activity, functioning regardless of p53 or ATM/ATR status, our results offer explanative power for understand how Chk1 inhibitors mediate single-agent anticancer efficacy. Further, they define CIP2A-PP2A status in cancer cells as a pharmacodynamic marker for their response to Chk1-targeted therapy.