Targeting TLK2 inhibits the progression of gastric cancer by reprogramming amino acid metabolism through the mTOR/ASNS axis

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 signi cantly 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 con rmed 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 con rmed that TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted the expression of ATF4. Finally, we found kinase inhibitor Fostamatinib can signi cantly 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.

Overexpression of tousled-like kinase 2 predicts poor prognosis in HBV-related hepatocellular carcinoma patients after radical resection

“…Overexpressed TLK2 binds to ATF4 to enhance asparagine synthetase (ASNA) transcription level and prevent ubiquitination of ASNA, thus promoting the progression of gastric cancer (GC) by reprogramming amino acid metabolism. Inhibiting TLK2 activity by the mTOR/ASNS axis will result in a suppression of GC cell proliferation and invasion (Wang et al, 2023). These studies showed TLK2 may serve as a potential biomarker for poor prognosis in certain cancers, while its inhibition demonstrates potential for cancer therapy.…”

“…Chromosome instability is one of the earliest genetic changes in precancerous lesions. However, TLK2 overexpression is common in certain tumors, correlating with adverse clinical outcomes (Kim et al, 2016b;Lin et al, 2019;Wang et al, 2023). There are no studies have been reported to explore the effects and possible pathogenesis of TLK2 in HBV-related HCC.…”