PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer
| Autor: | Nirzari Gupta, Sooryanarayana Varambally, Darshan S. Chandrashekar, Balabhadrapatruni V. S. K. Chakravarthi, Prachi Bajpai, Cherlene Y. Hardy, Hyung-Gyoon Kim, Sai Akshaya Hodigere Balasubramanya, Sameer Al Diffalha, Sumit Agarwal, Amr Elkholy, Michael Behring, Upender Manne |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Purine Cancer Research Colorectal cancer epithelial mesenchymal transition JQ1 Cell colorectal cancer PAICS lcsh:RC254-282 Article Metastasis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation metastasis Medicine Epithelial–mesenchymal transition Gene knockdown Phosphoribosylaminoimidazole carboxylase business.industry miR-128 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease digestive system diseases 030104 developmental biology medicine.anatomical_structure Oncology chemistry 030220 oncology & carcinogenesis Cancer research business |
| Zdroj: | Cancers Cancers, Vol 12, Iss 4, p 772 (2020) Volume 12 Issue 4 |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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