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Article

PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer

1
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL Birmingham, AL 35233, USA
2
Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL Birmingham, AL 35233, USA
3
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL Birmingham, AL 35233, USA
4
O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL Birmingham, AL 35233, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the manuscript writing.
Cancers 2020, 12(4), 772; https://doi.org/10.3390/cancers12040772
Received: 20 February 2020 / Revised: 18 March 2020 / Accepted: 23 March 2020 / Published: 25 March 2020
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. View Full-Text
Keywords: colorectal cancer; PAICS; epithelial mesenchymal transition; miR-128; metastasis; JQ1 colorectal cancer; PAICS; epithelial mesenchymal transition; miR-128; metastasis; JQ1
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MDPI and ACS Style

Agarwal, S.; Chakravarthi, B.V.S.K.; Behring, M.; Kim, H.-G.; Chandrashekar, D.S.; Gupta, N.; Bajpai, P.; Elkholy, A.; Balasubramanya, S.A.H.; Hardy, C.; Diffalha, S.A.; Varambally, S.; Manne, U. PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer. Cancers 2020, 12, 772. https://doi.org/10.3390/cancers12040772

AMA Style

Agarwal S, Chakravarthi BVSK, Behring M, Kim H-G, Chandrashekar DS, Gupta N, Bajpai P, Elkholy A, Balasubramanya SAH, Hardy C, Diffalha SA, Varambally S, Manne U. PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer. Cancers. 2020; 12(4):772. https://doi.org/10.3390/cancers12040772

Chicago/Turabian Style

Agarwal, Sumit, 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, and Upender Manne. 2020. "PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer" Cancers 12, no. 4: 772. https://doi.org/10.3390/cancers12040772

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