ABSTRACT: In the past, animal experiments with rats, by depleting various amino acids in the diet, have shown that a deficiency of methionine inhibits tumor growth at the individual level and that methionine is important in the development and progression of cancer. This methionine is one of the essential amino acids and is the initiation codon that initiates protein translation from mRNA. Methionine is known to be converted to SAM, which is required for nucleic acid synthesis in cancer. Tumors are underdeveloped in an environment deficient in methionine, which is known as the "Hoffman effect". In fact, past reports have shown that in the absence of methionine, tumor growth is suppressed, and methionine has recently been shown to be essential in cancer stem cells or "tumor initiating cells". In addition, the focus on methionine in cancer is said to influence tumor-cell metabolism, histone patterns, and T cell immunity in the cancer microenvironment. In cancer immunity, not only methionine but also its upstream pathways are said to be involved. Tryptophan/niacin, which is located upstream of the methionine cycle, is metabolized to form nicotinamide, and MNAM is formed from the SAM and nicotinamide via nicotinamide N-methyltransferase (NNMT). NNMT and MNAM have been reported to participate in the mechanism of inhibition of the apoptosis signal-regulated kinase 1-p38 MAPK pathway, resulting in increased colon cancer cell resistance to 5-FU. NNMTs promote nicotinamide adenine dinucleotide depletion and epigenetic reprogramming, which have been implicated in the development of metabolic plasticity, circumvention of the major tumor suppressive process of cellular senescence, acquisition of stem cell properties, and resistance to therapy and poor clinical outcomes. Also, MNAM synthesized in this methionine cycle is said to suppress T cells and promote cancer. Hence, we implanted the colon cancer cell line HT-29 cultured in normal medium with all nutrients into NOD SCID mice and kept them for 2 weeks on a diet without the aforementioned methionine/tryptophan/niacin. Afterwards, tumors were removed and RNA-sequencing was performed, and a marked increase in the expression of RN7SL1, a non-coding RNA, was observed.
