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 output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4833-4842
Number of pages10
JournalTumor Biology
Volume36
Issue number6
DOIs
Publication statusPublished - Feb 1 2015
Externally publishedYes

Fingerprint

PTEN Phosphohydrolase
Ribonucleotide Reductases
Protein Subunits
Colorectal Neoplasms
Up-Regulation
Neoplasm Metastasis
Holoenzymes
Transcriptional Activation
Neoplasms
Deoxyribonucleotides
Chromosomes, Human, Pair 10
Cadherins
Phosphoric Monoester Hydrolases
Catalytic Domain
Phosphorylation
Cell Proliferation

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Medicine(all)

Cite this

Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis. / Qi, Hongyan; Lou, Meng; Chen, Yuexia; Liu, Xiyong; Chen, Naiming; Shan, Jianzhen; Ling, Zhiqiang; Shen, Jing; Zhu, Lijun; Yen, Yun; Zheng, Shu; Shao, Jimin.

In: Tumor Biology, Vol. 36, No. 6, 01.02.2015, p. 4833-4842.

Research output: Contribution to journalArticle

Qi, H, Lou, M, Chen, Y, Liu, X, Chen, N, Shan, J, Ling, Z, Shen, J, Zhu, L, Yen, Y, Zheng, S & Shao, J 2015, 'Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis', Tumor Biology, vol. 36, no. 6, pp. 4833-4842. https://doi.org/10.1007/s13277-015-3137-4
Qi, Hongyan ; Lou, Meng ; Chen, Yuexia ; Liu, Xiyong ; Chen, Naiming ; Shan, Jianzhen ; Ling, Zhiqiang ; Shen, Jing ; Zhu, Lijun ; Yen, Yun ; Zheng, Shu ; Shao, Jimin. / Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis. In: Tumor Biology. 2015 ; Vol. 36, No. 6. pp. 4833-4842.
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AU - Chen, Naiming

AU - Shan, Jianzhen

AU - Ling, Zhiqiang

AU - Shen, Jing

AU - Zhu, Lijun

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AU - Zheng, Shu

AU - Shao, Jimin

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N2 - 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.

AB - 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.

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