α-Tomatine Inhibits Proliferation, Metastasis, Drug Resistance and Immune Infiltration Through the PI3K-AKT-MAPK Axis in Gastric Cancer
Abstract Background: α-Tomatine, a naturally existing steroidal glycoalkaloid in immature green tomatoes, had anticarcinogenic performances in various types of cancer cells. Within this study, we aimed to investigate the efficacy and potential molecular mechanism of α-tomatine in gastric cancer (GC) and the association with immune infiltration and prognosis.Methods: We used human GC cells MGC803, BGC823, SGC7901 and SGC7901/DDP to evaluate the cell functions of α-tomatine, and the molecular mechanisms of α-tomatine were investigated by qRT-PCR and western blotting analysis. Timer database was used to analyzed the correlation of targets repressed by α-tomatine, immune infiltration and prognosis. Results: Results showed that α-tomatine strongly inhibited PI3K-AKT and MAPK signaling pathways, thereby repressing the proliferation and metastasis of GC cells with different differentiations and cisplatin resistance. The inhibitory effect of α-tomatine on TWIST, Slug and PARP in SGC7901/DDP cells also suggested α-tomatine provided a feasible approach for confronting metastasis of clinical cisplatin resistant cases. Immunologically, α-tomatine could partially modulate the process and consequences of immune infiltration based on the correlation between 65 genes corresponding to interacting proteins and immune cell infiltration. α-Tomatine could improve prognosis of GC patients by inhibiting AKT3, VIM, FN1 and SNAI2, and at least partially counteract immune dysfunction triggered by macrophage infiltration. Conclusion: Strategies for treating GC should not be restricted to single, repetitive drug use, they should be predisposed to emerging, multi-target drugs. GC was highly susceptible to α-tomatine suggesting that α-tomatine could be used as an emerging and promising approach to confront GC.