Mulberrin suppresses gastric cancer progression and enhances chemosensitivity to oxaliplatin through HSP90AA1/PI3K/AKT axis.

Background: Mulberrin, a natural flavonoid featured with two isopentenyl groups, is derived from the mulberry family. Although previous researches have uncovered various properties of mulberrin, including the antioxidant, hypoglycemic, antibacterial, food-preserving, skin-whitening and life-extending effects in nematode, its potential therapeutic application and the underlying mechanism in gastric cancer (GC) remains largely unexplored.

Purpose: This research intends to examine the anti-tumoral effects of mulberrin and reveal the molecular mechanism through which mulberrin inhibits the GC progression.

Methods: To detect the proliferative of GC cells co-incubated with mulberrin, MTT, EdU, and colony formation assays were conducted. The migration and invasion capabilities of GC cells co-incubated with mulberrin were assessed using wound healing and Transwell assay experiments. Flow cytometry and western blot were utilized to depict changes in the cell cycle and protein expression of associated cyclins. The interaction between mulberrin and HSP90AA1 was accomplished through auto-dock molecular docking, CETSA and DARTS assays. The subcutaneous tumor model was constructed with NOD/SCID mice to detect the tumorigenic potential of GC cells. The drug synergetic effect of mulberrin and oxaliplatin was analyzed using the Jin's formula.

Results: Mulberrin effectively inhibited GC cell proliferation by inducing cell cycle arrest at G0/G1 phase. In addition, mulberrin significantly repressed the migration and invasion capacities of GC cells via reducing HSP90AA1 expression, leading to inhibition of the PI3K/AKT pathway and EMT process, hence curtailing proliferation, migration and invasion capacities of GC cells. Furthermore, mulberrin diminished the tumorigenic potential of GC cells, an effect mitigated by HSP90AA1 restoration. Notably, combining mulberrin with oxaliplatin yielded a synergistic inhibitory effect on GC cells, surpassing the efficacy of either agent used alone.

Conclusion: Mulberrin suppresses proliferation, migration and invasion of GC cells by directly targeting and reducing HSP90AA1 to inhibit the PI3K/AKT pathway and EMT process. Additionally, mulberrin increases the sensitivity of GC cells to oxaliplatin. Together, these findings uncover a latent use of mulberrin as a promising therapeutic drug that may be included in anti-GC strategies for the treatment of GC patients.