Tumor Biology

, Volume 36, Issue 6, pp 4833–4842 | Cite as

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

  • Hongyan Qi
  • Meng Lou
  • Yuexia Chen
  • Xiyong Liu
  • Naiming Chen
  • Jianzhen Shan
  • Zhiqiang Ling
  • Jing Shen
  • Lijun Zhu
  • Yun Yen
  • Shu Zheng
  • Jimin Shao
Research Article

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.

Keywords

Ribonucleotide reductase large subunit M1 Non-enzymatic role Colorectal cancer Metastasis 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81090421, 30873094, 81372138, and 81000893), the 863 National High Technology Research and Development Program of China (2012AA020206), and the Natural Science Foundation of Zhejiang Province (LY13H 160001, Y2110111).

Conflicts of interest

None

Supplementary material

13277_2015_3137_Fig5_ESM.gif (45 kb)
Table S1

Clinico-pathologic parameters of 35 CRC patients from whom paired cancer/normal samples were obtained. (GIF 45 kb)

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High resolution image (EPS 695 kb)
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Table S2

Clinico-pathologic parameters of 105 patients with primary CRC. (EPS 695 kb) (GIF 44 kb)

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High resolution image (EPS 729 kb)
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Table S3

Clinico-pathologic parameters of 37 patients with liver metastatic CRC. (EPS 729 kb) (GIF 40 kb)

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High resolution image (EPS 727 kb)
13277_2015_3137_Fig8_ESM.gif (106 kb)
Figure S1

RRM1 and its mutant decreased the FAK phosphorylation and increased E-cadherin expression in a PTEN dependent manner in HT29 cells. a Percentage of closure wound-healing assay 48 h after after co-transfection of PTEN-siRNA and wild-type or Y738F-mutant RRM1 in CRC HT29 cells. b Western blots of phosphorylation levels of FAK after overexpression of the wild-type or Y738F-mutant RRM1 in HT29 cells. c Effects of PTEN-siRNA on E-cadherin protein expression in HT29 cells by Western blots. *P <0.05. (EPS 727 kb) (GIF 106 kb)

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High resolution image (EPS 3354 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • 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. 1.Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Research Center for Air Pollution and HealthZhejiang University School of MedicineHangzhouChina
  2. 2.Division of Clinical and Molecular PharmacologyCity of Hope National Medical CenterDuarteUSA
  3. 3.Cancer InstituteZhejiang UniversityHangzhouChina
  4. 4.Cancer InstituteZhejiang Cancer HospitalHangzhouChina

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