Abstract

L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine's and piperazine's nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.

Highlights

  • Colorectal cancer (CRC) remains one of the most common and lethal cancers, despite recent progress in the disease prevention and patients’ management [1]

  • L-arginine/NO pathway metabolites at systemic level and their utility as diagnostic and prognostic tools in colorectal cancer (CRC) has already been demonstrated [7]

  • Local expression of Nitric oxide synthase-2 (NOS2) is upregulated in inflammatory bowel conditions [6] and linked with increased risk of CRC development [35]

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Summary

Introduction

Colorectal cancer (CRC) remains one of the most common and lethal cancers, despite recent progress in the disease prevention and patients’ management [1]. Latest advances in various “-omics”, genomics and proteomics, have improved our understanding of molecular landscape of CRC. There are few resulting biomarkers to aid diagnosis and clinical-decision making or which serve as molecular targets for chemoprevention and treatment [2]. Metabolic reprogramming is one of eight recognized cancer hallmarks [3]. Cancer metabolism is highly flexible and cancer typeand context-dependent [4]. Further research employing quantitative metabolic profiling is needed to translate metabolic abnormalities into clinical practice successfully [5]

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