1946P - SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via inhibiting cystine transportation in gastric cancer

Background

The aims of the study was to reveal the mechanisms of SLC7A9 regulating ferroptosis in gastric cancer cells and explore new treatment strategies for gastric cancer (GC) by targeting ferroptosis.

Methods

The expression of SLC7A9 in tumor tissues and matched adjacent non-tumor tissues of GC was detected by IHC staining, and its correlation with the outcomes of patients with GC was analyzed. Metabolomic analysis, RNA sequencing, western blotting and GSH/GSSG detection were used to identify the function of SLC7A9 in ferroptosis and GSH metabolism. Suppression of SLC7A9-induced ferroptosis was validated in PDO and PDX models.

Results

The higher SLC7A9 expression in tumor tissue was associated with the worse prognosis of GC patients. Down-regulating SLC7A9 expression inhibited the proliferation of GC cells, reduced the level of GSH, and decreased the ratio of GSH/GSSG. SLC7A9-KD induced cell death could be reversed by ferroptosis inhibitors ferrostatin-1 or liproxstatin-1, and SLC7A9 over-expression attenuated ferroptosis caused by ferroptosis inducer erastin and reversed the erastin-induced decreased ratio of GSH/GSSG. SLC7A9-KD decreased the expression of GPX4, while SLC7A9 over-expression increased the expression of GPX4. P53 was a repressive transcription factor of SLC7A9, and TP53 mutation might lead to increase the expression of SLC7A9. In PDO and PDX models, erastin induced more ferroptosis in the lower SLC7A9 expression tumor tissues than that in the higher SLC7A9 expression. In the PDX model of GC, intratumoral injection of lentivirus with shSLC7A9, we found that shSLC7A9 inhibited tumor growth significantly. When PDX model of GC was combined treated by shSLC7A9 lentivirus and erastin the synergistic therapeutic effect was got.

Conclusions

The expression of SLC7A9 was up-regulated in the tumor tissues of GC, and the expression level of SLC7A9 in tumor tissues was negatively correlated with the overall survival of the patients. SLC7A9 could induce the resistance to ferroptosis in GC cells. P53 might act as a repressive transcription factor to regulate the expression of SLC7A9 in GC. Targeted inhibition of SLC7A9 could induce ferroptosis of GC cells.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

Funding

National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.