title: Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis.
abstract: 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 T1-3 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.
authors: 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.
authors: Hongyan
authors: H
authors: Qi
authors: Meng
authors: M
authors: Lou
authors: Yuexia
authors: Y
authors: Chen
authors: Xiyong
authors: X
authors: Liu
authors: Naiming
authors: N
authors: Chen
authors: Jianzhen
authors: J
authors: Shan
authors: Zhiqiang
authors: Z
authors: Ling
authors: Jing
authors: J
authors: Shen
authors: Lijun
authors: L
authors: Zhu
authors: Yun
authors: Y
authors: Yen
authors: Shu
authors: S
authors: Zheng
authors: Jimin
authors: J
authors: Shao
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics*; D012262:Ribonucleoside Diphosphate Reductase; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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