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Outline
To investigate the capacity of oxaliplatin (OXA) in inducing cuproptosis in treatment of gastric cancer and explore the underlying mechanisms.
Kaplan-Meier Plotter was used to analyze the data in UALCAN database to explore the key regulatory proteins involved in cuproptosis, dihydrolipoamide S-acetyltransferase (DLAT), ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS) in gastric cancer. The cytotoxic effects of OXA alone and in combination with copper chelator tetrathiomolybdate (TTM) were determined using CCK-8 assays. Immunofluorescence assay and Western blotting were employed to assess the mitochondrial oligomerization of DLAT and the expression levels of FDX1 and LIAS. Intracellular copper levels were measured using a copper-specific fluorescent probe following treatment with OXA and TTM. A subcutaneous tumor model was established through subcutaneous injection of gastric cancer MKN-45 cells in SPF-grade female Balb/c nude mice (5~6 weeks old, weighing 18~25 g). Then the nude mice were randomly assigned into control group, OXA treatment group (intraperitoneal injection), and OXA and tetrasolybdate (TTM) treatment group. Tumor size was monitored regularly to plot a tumor growth curve. Tumor tissues were harvested, embedded in paraffin, sectioned and then subjected to immunohistochemical (IHC) staining to evaluate expression of FDX1 and LIAS. Copper staining was performed to assess copper levels in tumor tissues.
The expression levels of FDX1 and DLAT were significantly elevated in gastric cancer tissues than normal tissues (P<0.001), and the expression levels of FDX1, DLAT and LIAS were associated with the prognosis of gastric cancer. OXA treatment inhibited cell proliferation in both MKN-45 and BGC-823 cells, with the IC50 values of 44.89 and 19.02 μmol/L, respectively. Its cytotoxicity was significantly attenuated by TTM (P<0.001). OXA induced pronounced mitochondrial oligomerization of DLAT, intracellular copper accumulation, and reduced FDX1/LIAS expression. In nude mice of transplanted tumor, OXA monotherapy significantly suppressed tumor growth (P<0.01), which was weakened by TTM treatment (P<0.001), and decreased the protein levels of FDX1 and LIASr than those in the control and OXA+TTM groups. Copper staining revealed elevated intracellular copper levels in the OXA-treated group, consistent with in vitro findings.
OXA inhibits the progression of gastric cancer by inducing cuproptosis in tumor cells.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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