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- W4327716295 abstract "Abstract Several recent studies suggested that TLKs are related to tumor progression. However, the function and action mechanism of TLK2 in GC remain elusive. We observed that TLK2 was significantly upregulated in GC and acted as an independent prognostic factor in GC patients. In line with these results, TLK2 silencing markedly reduced GC aggressiveness, whereas its overexpression had the opposite effect. IP-MS suggested that the effect of TLK2 expression on GC was mainly associated with metabolism reprogramming. TLK2 knockdown suppressed amino synthesis through downregulating the mTORC1 pathway and ASNS expression in GC. Mechanistically, mTORC1 directly interacted with ASNS and inhibited its protein degradation. Further experiments confirmed that ASNS protein degradation was ubiquitination degradation rather than degradation through autophagy. Inhibiting and activating the mTORC1 pathway can upregulate and downregulate ASNS ubiquitination, respectively. Moreover, the mTORC1 pathway can reverse the protein regulation of ASNS by TLK2. Notably, TLK2 regulated the ASNS mRNA levels. Further evidence confirmed that TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted the expression of ATF4. Finally, we found kinase inhibitor Fostamatinib can significantly inhibit the proliferation, invasion, and migration of GC cells by inhibiting TLK2 enzyme activity. Taken together, this study reveals a novel functional link between TLK2, the mTORC1/ASNS axis, and GC. Therefore, TLK2 could be a potential therapeutic approach for GC target therapy." @default.
- W4327716295 created "2023-03-18" @default.
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- W4327716295 date "2023-03-17" @default.
- W4327716295 modified "2023-09-29" @default.
- W4327716295 title "Targeting TLK2 inhibits the progression of gastric cancer by reprogramming amino acid metabolism through mTOR/ASNS axis" @default.
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- W4327716295 doi "https://doi.org/10.21203/rs.3.rs-2610117/v1" @default.
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