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

研究成果: 雜誌貢獻文章

8 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)4833-4842
頁數10
期刊Tumor Biology
36
發行號6
DOIs
出版狀態已發佈 - 二月 1 2015
對外發佈Yes

指紋

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

ASJC Scopus subject areas

  • Cancer Research
  • Medicine(all)

引用此文

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.

於: Tumor Biology, 卷 36, 編號 6, 01.02.2015, p. 4833-4842.

研究成果: 雜誌貢獻文章

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, 卷 36, 編號 6, 頁 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. 於: Tumor Biology. 2015 ; 卷 36, 編號 6. 頁 4833-4842.
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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.",
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T1 - Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis

AU - Qi, Hongyan

AU - Lou, Meng

AU - Chen, Yuexia

AU - Liu, Xiyong

AU - Chen, Naiming

AU - Shan, Jianzhen

AU - Ling, Zhiqiang

AU - Shen, Jing

AU - Zhu, Lijun

AU - Yen, Yun

AU - Zheng, Shu

AU - Shao, Jimin

PY - 2015/2/1

Y1 - 2015/2/1

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.

KW - Colorectal cancer

KW - Metastasis

KW - Non-enzymatic role

KW - Ribonucleotide reductase large subunit M1

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