Overexpression of CPS1 is an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy

Abstract

Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but stratification of risk and final outcomes remain suboptimal. In view of the fact that glutamine metabolism is usually altered in cancer, we profiled and validated the significance of genes involved in this pathway in rectal cancers treated with CCRT. From a published transcriptome of rectal cancers (GSE35452), we focused on glutamine metabolic process-related genes (GO:0006541) and found upregulation of carbamoyl phosphate synthetase 1 (CPS1) gene most significantly predicted poor response to CCRT. We evaluated the expression levels of CPS1 using immunohistochemistry to analyze tumor specimens obtained during colonoscopy from 172 rectal cancer patients. Expression levels of CPS1 were further correlated with major clinicopathological features and survivals in this validation cohort. To further confirm CPS1 expression levels, Western blotting was performed for human colon epithelial primary cell (HCoEpiC) and four human colon cancer cells, including HT29, SW480, LoVo, and SW620. CPS1 overexpression was significantly related to advanced posttreatment tumor (T3, T4; P = 0.006) and nodal status (N1, N2; P < 0.001), and inferior tumor regression grade (P = 0.004). In survival analyses, CPS1 overexpression was significantly associated with shorter disease-specific survival (DSS) and metastasis-free survival (MeFS). Furthermore, using multivariate analysis, it was also independently predictive of worse DSS (P = 0.021, hazard ratio = 2.762) and MeFS (P = 0.004, hazard ratio = 3.897). CPS1 protein expression, as detected by Western blotting, is more abundant in colon cancer cells than nonneoplastic HCoEpiC. Overexpression of CPS1 is associated with poor therapeutic response and adverse outcomes among rectal cancer patients receiving CCRT, justifying the potential theranostic value of CPS1 for such patients.

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

“…CPS1 is expressed mainly in intestinal epithelial cells and liver cells, as well as several types of cancer including liver, colorectal, stomach, cervical, and pancreatic cancer (29)(30)(31)(32)(33)(34)(35)(36)(37). Although expression of CPS1 protein has not been well studied in lung cancer, Kaufman ARTICLE (38).…”

“…Increased CPS1 expression is also associated with poor prognosis in cervical carcinoma (37) and rectal cancer (33). Of note, positive immunostaining of CPS1 was statistically significantly associated with poorer overall survival in stage I LADC.…”

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC

“…Celiktaş and colleagues demonstrated an additive effect of CPS1 knockdown with chemotherapy agents in LKB1-mutant NSCLC cells (23), suggesting that the role of CPS1 may be distinct in EGFR or EML4-ALK-driven lung cancer. In normal tissues, CPS1 is expressed abundantly in the liver and gastrointestinal tract (42,43); however, CPS1 has been reported to exhibit higher expression in multiple cancer types (25,44). More recently, CPS1 expression has been associated with KRAS/LKB1-mutant lung cancer cell growth (24).…”

“…Mechanistically, CPS1 has been shown to sustain pyrimidine levels and DNA synthesis in KRAS/LKB1 lung cancer cells (24). Moreover, overexpression of CPS1 in patients with colorectal cancer correlated with shorter disease-specific survival, shorter metastatic-free survival and poor therapeutic responses (25). In contrast to CPS1, another urea cycle enzyme, argininosuccinate synthase 1 (ASS1), has been reported to be repressed in several types of cancers including osteosarcomas, melanoma, and hepatocellular carcinomas (26).…”

Network Mapping of Molecular Biomarkers Influencing Radiation Response in Rectal Cancer

“…Cell-surface receptor signaling ABCC4, 53 CD34 37 , CD44, 10,14 CD133, 14,56 CD166, 14 CXCR4, 40 EGFR, 14,15,22,39 EpCAM, 14 GHRH-R, 21 HER-2, 45,57 16,17,37,45,56,62 ALDH1, 14,63 HMGCS2, 64,65 HSD17B2, 65 MMP9, 43 phospho-Akt, 21 GLUT-1, 18,40 CPS1, 66 asparagine synthetase 67…”