Abstract
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.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the USA, accounting for 17% of all cancer deaths; it is predicted to cause 51,020 deaths during 2019 [1]
These results demonstrate that colorectal cancer (CRC) overexpress the phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) protein irrespective of the disease stage
We previously reported that PAICS, an enzyme of de novo purine biosynthesis pathway, triple-negative breast cancer is associated with lung cancers [14], prostate adenocarcinomas [15], and bladder cancers [16] and
Summary
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the USA, accounting for 17% of all cancer deaths; it is predicted to cause 51,020 deaths during 2019 [1]. Stagein several independent profiling studies (Figure 1A) Such studies acquired from Skrzypczak wise expression provided by UALCAN showed that PAICS wasexpression overexpressed all purine stages datasets [21] available in Oncomine, showed, for CRCs, increased of theacross de novo compared to normal tissues and that expression was independent of the pathological stage Our analyses show higher expression in all pathological stages of CRC (HCT116p53-wt, HCT116p53-null, and SW480p53-mut), relative to CRL1807 SV-40 transformed colon cells tissues compared with matched normal colorectal tissues (Figure 2A). The immunofluorescence analysis revealed that PAICS protein expression was predominantly localized in the cytoplasm of HCT116p53-wt , HCT116p53-null , and SW480p53-mut cells (Figure 2D) and HT29p53-mut (Figure S2F) These results demonstrate that CRCs overexpress the PAICS protein irrespective of the disease stage.
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