Marine fungus-derived alkaloid inhibits the growth and metastasis of gastric cancer via targeting mTORC1 signaling pathway

Abstract

Gastric cancer (GC) is a highly aggressive and deadly disease worldwide. Given the limitations of current treatments, it is crucial to discover more effective antitumor drugs. Here, we demonstrated that arthpyrone M (Art-M), a novel 4-hydroxy-2-pyridone alkaloid derived from the marine fungus Arthrinium arundinis, inhibited the proliferation, invasion and migration of GC both in vivo and in vitro. The underlying mechanism of Art-M in GC cells was explored by RNA-sequencing analysis, qRT-PCR and immunoblotting, which demonstrated that Art-M significantly suppressed the mTORC1 pathway by decreasing phosphorylated mTOR and p70S6K. Moreover, Art-M feedback increased the activities of AKT and ERK. Co-immunoprecipitation and immunoblotting analysis revealed that Art-M induced dissociation of Raptor from mTOR and promoted Raptor degradation, leading to the inhibition of mTORC1 activity. Art-M was identified as a novel and potent mTORC1 antagonist. Furthermore, Art-M enhanced GC cell sensitivity to apatinib, and the combination of Art-M and apatinib showed better efficacy in the treatment of GC. Taken together, these results demonstrate that Art-M is a promising candidate drug for the treatment of GC by suppressing the mTORC1 pathway.