PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer
The identification of colorectal cancer (CRC) molecular targets is needed for the development of drugs that improve patient survival. We investigated the functional role of phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a de novo purine...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/772 |
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| author | Sumit Agarwal Balabhadrapatruni V. S. K. Chakravarthi Michael Behring Hyung-Gyoon Kim Darshan S. Chandrashekar Nirzari Gupta Prachi Bajpai Amr Elkholy Sai A. H. Balasubramanya Cherlene Hardy Sameer Al Diffalha Sooryanarayana Varambally Upender Manne |
| author_facet | Sumit Agarwal Balabhadrapatruni V. S. K. Chakravarthi Michael Behring Hyung-Gyoon Kim Darshan S. Chandrashekar Nirzari Gupta Prachi Bajpai Amr Elkholy Sai A. H. Balasubramanya Cherlene Hardy Sameer Al Diffalha Sooryanarayana Varambally Upender Manne |
| author_sort | Sumit Agarwal |
| collection | DOAJ |
| description | The identification of colorectal cancer (CRC) molecular targets is needed for the development of drugs that improve patient survival. We investigated the functional role of phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a de novo purine biosynthetic enzyme involved in DNA synthesis, in CRC progression and metastasis by using cell and animal models. Its clinical utility was assessed in human CRC samples. The expression of PAICS was regulated by miR-128 and transcriptionally activated by Myc in CRC cells. Increased expression of PAICS was involved in proliferation, migration, growth, and invasion of CRC cells irrespective of the p53 and microsatellite status. In mice, the depletion of PAICS in CRC cells led to reduced tumor growth and metastatic cell dissemination to the liver, lungs, and bone. Positron emission tomography imaging showed significantly reduced metastatic lesions in stable PAICS knockdown CRC cells. In cells with PAICS knockdown, there was upregulation of the epithelial mesenchymal transition marker, E-cadherin, and bromodomain inhibitor, JQ1, can target its increased expression by blocking Myc. PAICS was overexpressed in 70% of CRCs, and was associated with poor 5-year survival independent of the pathologic stage, patient's race, gender, and age. Overall, the findings point to the usefulness of PAICS targeting in the treatment of aggressive colorectal cancer. |
| first_indexed | 2024-03-12T10:54:29Z |
| format | Article |
| id | doaj.art-6577980582794f799c1e381b8b8f7709 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:54:29Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6577980582794f799c1e381b8b8f77092023-09-02T06:35:00ZengMDPI AGCancers2072-66942020-03-0112477210.3390/cancers12040772cancers12040772PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal CancerSumit Agarwal0Balabhadrapatruni V. S. K. Chakravarthi1Michael Behring2Hyung-Gyoon Kim3Darshan S. Chandrashekar4Nirzari Gupta5Prachi Bajpai6Amr Elkholy7Sai A. H. Balasubramanya8Cherlene Hardy9Sameer Al Diffalha10Sooryanarayana Varambally11Upender Manne12Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USAThe identification of colorectal cancer (CRC) molecular targets is needed for the development of drugs that improve patient survival. We investigated the functional role of phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a de novo purine biosynthetic enzyme involved in DNA synthesis, in CRC progression and metastasis by using cell and animal models. Its clinical utility was assessed in human CRC samples. The expression of PAICS was regulated by miR-128 and transcriptionally activated by Myc in CRC cells. Increased expression of PAICS was involved in proliferation, migration, growth, and invasion of CRC cells irrespective of the p53 and microsatellite status. In mice, the depletion of PAICS in CRC cells led to reduced tumor growth and metastatic cell dissemination to the liver, lungs, and bone. Positron emission tomography imaging showed significantly reduced metastatic lesions in stable PAICS knockdown CRC cells. In cells with PAICS knockdown, there was upregulation of the epithelial mesenchymal transition marker, E-cadherin, and bromodomain inhibitor, JQ1, can target its increased expression by blocking Myc. PAICS was overexpressed in 70% of CRCs, and was associated with poor 5-year survival independent of the pathologic stage, patient's race, gender, and age. Overall, the findings point to the usefulness of PAICS targeting in the treatment of aggressive colorectal cancer.https://www.mdpi.com/2072-6694/12/4/772colorectal cancerpaicsepithelial mesenchymal transitionmir-128metastasisjq1 |
| spellingShingle | Sumit Agarwal Balabhadrapatruni V. S. K. Chakravarthi Michael Behring Hyung-Gyoon Kim Darshan S. Chandrashekar Nirzari Gupta Prachi Bajpai Amr Elkholy Sai A. H. Balasubramanya Cherlene Hardy Sameer Al Diffalha Sooryanarayana Varambally Upender Manne PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer Cancers colorectal cancer paics epithelial mesenchymal transition mir-128 metastasis jq1 |
| title | PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer |
| title_full | PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer |
| title_fullStr | PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer |
| title_full_unstemmed | PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer |
| title_short | PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer |
| title_sort | paics a purine nucleotide metabolic enzyme is involved in tumor growth and the metastasis of colorectal cancer |
| topic | colorectal cancer paics epithelial mesenchymal transition mir-128 metastasis jq1 |
| url | https://www.mdpi.com/2072-6694/12/4/772 |
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