Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis

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• 作者：Hongyan Qi ; Meng Lou ; Yuexia Chen ; Xiyong Liu ; Naiming Chen ; Jianzhen Shan…
• 关键词：Ribonucleotide reductase large subunit M1 ; Non ; enzymatic role ; Colorectal cancer ; Metastasis
• 刊名：Tumor Biology
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：36
• 期：6
• 页码：4833-4842
• 全文大小：1,858 KB
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• 作者单位：Hongyan Qi (1)
  Meng Lou (1)
  Yuexia Chen (1)
  Xiyong Liu (2)
  Naiming Chen (1)
  Jianzhen Shan (3)
  Zhiqiang Ling (4)
  Jing Shen (1)
  Lijun Zhu (1)
  Yun Yen (2)
  Shu Zheng (3)
  Jimin Shao (1)
  
  1. Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou, 310058, China
  2. Division of Clinical and Molecular Pharmacology, City of Hope National Medical Center, Duarte, CA, 91010, USA
  3. Cancer Institute, Zhejiang University, Hangzhou, 310058, China
  4. Cancer Institute, Zhejiang Cancer Hospital, Hangzhou, 311118, China
  
• 刊物主题：Cancer Research;
• 出版者：Springer Netherlands
• ISSN：1423-0380

文摘

Ribonucleotide reductase large subunit M1 (RRM1) forms a holoenzyme with small subunits to provide deoxyribonucleotides for DNA synthesis and cell proliferation. Here, we reported a non-RR role of the catalytic subunit protein RRM1 and related pathway in inhibiting colorectal cancer (CRC) metastasis. Ectopic overexpression of the wild-type RRM1, and importantly, its Y738F mutant that lacks RR enzymatic activity, prevented the migration and invasion of CRC cells by promoting phosphatase and tensin homolog on chromosome 10 (PTEN) transactivation. Furthermore, overexpression of the wild-type and RR-inactive mutant RRM1 similarly reduced the phosphorylation of Akt and increased the E-cadherin expression in CRC cells, which were blocked by PTEN knockdown attenuation. Examination of clinical CRC specimens demonstrated that both RRM1 protein expression and RR activity were elevated in most cancer tissues compared to the paired normal tissues. However, while RR activity did not change significantly in different cancer stages, the RRM1 protein level was significantly increased at stages T1- but decreased at stage T4, in parallel with the PTEN expression level and negatively correlated with invasion and liver metastasis. Thus, we propose that RRM1 protein can inhibit CRC invasion and metastasis at the advanced stage by regulating PTEN transactivation and its downstream pathways in addition to forming an RR holoenzyme for supporting cancer proliferation. Understanding of the seemingly contrary dual roles of RRM1 protein may further help to explain the complex mechanisms by which this key enzyme and its components are involved in cancer development.