Kynureninase induce cuproptosis resistance in gastric cancer progression through downregulating lipotic acid synthetase mediated non-canonical mechanism

Abstract

Background

Gastric cancer (GC) is among the most malignant tumors, with the lowest five-year survival rate, and limited treatment options. Kynureninase (KYNU), is a key molecule in tryptophan metabolism and promotes tumor progression and immunosuppression. Cuproptosis is a non-apoptotic cell death mechanism, primarily due to oxidative stress caused by copper ion accumulation, that is related to tumor progression and drug resistance. KYNU can inhibit ferroptosis of tumor cells by alleviating oxidative stress. Here, we explored whether KYNU can regulate the biological behavior of GC and cuproptosis.

Methods

Expression, prognostic association, and functional analysis of KYNU in GC and tumor-adjacent tissues were analyzed using data from The Cancer Genome Atlas and clinical specimens. Effects of KYNU on proliferation, invasion, metastasis, and cuproptosis of GC cells were detected by CCK8, clone formation, Transwell, and flow cytometry assays. Elesclomol (ES) combined with CuCl₂ were used to induce cuproptosis in GC cells. 3-hydroxyanthranilic acid (3-HA) was used to indicate KYNU function. Key cuproptosis genes were detected by qPCR and WB. The effects of KYNU on GC cell behavior and cuproptosis through lipoic acid synthetase (LIAS) were verified by stable overexpression and knockdown of LIAS.

Results

KYNU is highly expressed in GC, and high KYNU expression is an independent predictor of poor prognosis in patients with GC. KYNU can promote GC cell proliferation, invasion, metastasis, and cuproptosis resistance. 3-HA had a certain inhibitory effect on the expression of LIAS, but it was not significant. KYNU had no effect on the intracellular 3-HA level. KYNU expression was negatively correlated with that of LIAS, and promoted GC cell proliferation, invasion, metastasis, and cuproptosis resistance by downregulating LIAS.

Conclusions

KYNU can promote GC proliferation, invasion, metastasis, and cuproptosis resistance.This effect is not associated with its metabolite 3-HA, but is achieved by a non classical mechanisms that downregulating the expression of LIAS, a key gene of cuproptosis.