Nicotinamide N-methyltransferase in Non-small Cell Lung Cancer: Promising Results for Targeted Anti-cancer Therapy

Abstract

Lung cancer, predominantly non-small cell lung cancer (NSCLC), is currently the most common cause of malignancy-related death in the world. Despite advances in both detection and treatment, its incidence rate is still increasing. Therefore, effective strategies for early detection as well as molecular therapeutic targets are urgently needed. We focused on the enzyme nicotinamide N-methyltransferase (NNMT). NNMT expression levels were investigated in tumor, tumor-adjacent, and surrounding tissue samples of 25 patients with NSCLC by Real-Time PCR, Western blot analysis, and catalytic activity assay. NNMT enzyme activity in NSCLC was then correlated with clinicopathological characteristics. Results obtained showed NNMT upregulation (mRNA and protein) in tumor compared with both tumor-adjacent and surrounding tissue. Moreover, NSCLC displayed significantly higher activity levels than those determined in both tumor-adjacent and surrounding tissue. Interestingly, both tumor-adjacent and surrounding tissue samples of unfavorable cases (N+) seem to display higher activity levels than those of favorable NSCLCs (N0). The present work shows a marked increase of NNMT enzyme activity in NSCLC and suggests that normal-looking tissue of unfavorable cases seems to change toward cancer. Further studies may establish whether NNMT could represent a target for an effective anti-cancer therapy.

Identification and Characterization of Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma Cell Lines

“…An enhanced expression of NNMT has been reported in a number of cancers, such as glioblastoma [47], stomach adenocarcinoma [48,49], papillary thyroid cancers [50,51], renal [52,53], and oral squamous cell carcinomas [54][55][56], colorectal cancer [57], bladder [58], lung and pancreatic cancers [59][60][61]. In our previous works, we explored NNMT expression in renal cell carcinoma (ccRCC) [52], oral squamous cell carcinoma (OSCC) [54][55][56], urothelial carcinoma (UC) of the bladder [58] and non-small cell lung cancer (NSCLC) [60]. Although several cancers have been associated with abnormal NNMT expression, its role in cancer cell metabolism remains largely unknown.…”

Effects of Nicotinamide N-Methyltransferase on PANC-1 Cells Proliferation, Metastatic Potential and Survival Under Metabolic Stress

“…As a phase II metabolizing enzyme, NNMT is involved in the biotransformation of many drugs and xenobiotic compounds [6,7,21]. Abnormal NNMT expression has been reported in many human neoplasms including brain, nasopharynx, oral cavity, thyroid, lung, liver, stomach, kidney, bladder and colon [8,9,10,11,12,13,14,15,16,17,18]. Furthermore, a recent study showed that NNMT overexpression was associated with increased radioresistance via regulating nicotinamide metabolism [22].…”

“…It is predominantly expressed in liver and weakly expressed in other tissues like kidney, lung, skeletal muscle, placenta, heart and brain [6]. Abnormal expression of NNMT has been found in numerous cancers, including glioblastoma [8], hepatocellular carcinoma [9], thyroid carcinoma [10], gastric cancer [11], renal cell carcinoma [12], colorectal cancer [13], oral squamous cell carcinoma [14], bladder cancer [15], non-small cell lung cancer [16], and nasopharyngeal carcinoma [17]. These results suggest that NNMT may serve as a potential biomarker for tumor diagnosis and a new therapeutic target.…”

IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle

“…The top expressed gene other than SOCS3 under both treatment paradigms was PLA2G2A [type-II secretory phospholipase A2: sPLA 2 (AII)], an enzyme associated with acute respiratory distress syndrome (ARDS) (35,61,74). PLA2G2A expression was higher under IL-6 trans-signaling conditions compared with classical IL-6 conditions ( (58,59), IL13RA1 (interleukin 13 receptor alpha 1) (5), and SOD2 (superoxide dismutase 2) (41). OSMR (oncostatin M receptor), a member of the IL-6 receptor family (complexes with coreceptor gp130) (15), was significantly elevated under both treatment conditions.…”