TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling

Abstract

Copy number alterations are crucial for gastric cancer (GC) development. In this study, Tocopherol alpha transfer protein-like (TTPAL) was identified to be highly amplified in our primary GC cohort (30/86). Multivariate analysis showed that high TTPAL expression was correlated with the poor prognosis of GC patients. Ectopic expression of TTPAL promoted GC cell proliferation, migration, and invasion in vitro and promoted murine xenograft tumor growth and lung metastasis in vivo. Conversely, silencing of TTPAL exerted significantly opposite effects in vitro. Moreover, RNA-sequencing and co-immunoprecipitation (Co-IP) followed by liquid chromatograph-mass spectrometry (LC-MS) identified that TTPAL exerted oncogenic functions via the interaction of Nicotinamide-N-methyl transferase (NNMT) and activated PI3K/AKT signaling pathway. Collectively, TTPAL plays a pivotal oncogenic role in gastric carcinogenesis through promoting PI3K/AKT pathway via cooperating with NNMT. TTPAL may serve as a prognostic biomarker of patients with GC.

Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma

“…As a small molecule methyltransferase in the human body responsible for the N-methylation of the nicotinamide, NNMT has been reported to promote proliferation or migration of several malignant tumors, including gastric cancer, esophageal cancer and OSCC [ 13 , 14 , 16 ]. Previous studies reported the high expression of NNMT in OSCC patients was negatively associated with lymph node metastasis.…”

“…In recent years, NNMT has been reported to be involved in regulating multiple metabolic pathways by depleting methyl donors and producing active metabolites. NNMT is overexpressed in a variety of tumors and has been shown to promote progression and poor prognosis of several malignant tumors, such as gastric cancer, esophageal cancer and colorectal cancer [ 13 , 14 , 15 ]. For OSCC, Sartini D et al reported that NNMT was highly expressed in OSCC patients and was negatively associated with lymph node metastasis [ 16 ].…”

Prognostic value of nicotinamide adenine dinucleotide (NAD+) metabolic genes in patients with stomach adenocarcinoma based on bioinformatics analysis

“…Previous research showed that NNMT expression was substantially linked with GC stage, and increased stromal NNMT expression predicted poor prognosis in GC, which is consistent with our data ( 36 ). It is worth noting that Liu et al demonstrated that NNMT directly interacts with TTPAL to activate PI3K/AKT signaling to promote gastric carcinogenesis, hence partaking in cancer proliferation, invasion, metastasis and drug resistance ( 37 ). Likewise, AOX1 is one of the key enzymes in tryptophan catabolism, and deletion of AOX1 may lead to the accumulation of kynurenine and NADP ( 38 , 39 ).…”

Complex roles of nicotinamide N-methyltransferase in cancer progression

“…Their interaction indicated that NNMT was associated with PI3K/AKT pathway. Co-IP and confocal immunofluorescence experiments showed that NNMT interacted and co-localized with alpha-tocopherol transfer protein-like (TTPAL), which was upregulated and correlated with poor survival in gastric cancer [ 39 ]. Overexpression of TTPAL in gastric cancer cells upregulated NNMT, indicating that TTPAL stabilized NNMT in the PI3K/AKT signaling pathway [ 39 ].…”

“…Co-IP and confocal immunofluorescence experiments showed that NNMT interacted and co-localized with alpha-tocopherol transfer protein-like (TTPAL), which was upregulated and correlated with poor survival in gastric cancer [ 39 ]. Overexpression of TTPAL in gastric cancer cells upregulated NNMT, indicating that TTPAL stabilized NNMT in the PI3K/AKT signaling pathway [ 39 ]. In addition, Co-IP followed by mass spectrometry of mouse liver showed that the NNMT-interacted with betaine-homocysteine methyltransferase (BHMT), fructose 1,6 bisphosphatase 1 (FBP1), dihydroxyacetone kinase (DAK), methionine adenosyltransferase 1a (MAT1A), heat shock protein A8 (HSPA8), solute carrier transporter mitochondrial (citrate) (SLC25A1), selenium binding protein 2 (SELENBP2), and adenosylhomocysteinase (AHCY) [ 40 ].…”