Src acts as the target of matrine to inhibit the proliferation of cancer
cells by regulating phosphorylation signaling pathways
Background and Purpose: Identification of accurate targets is essential
for a successful development of targeted therapy in cancer. Studies have
shown that matrine has antitumor activity against many types of cancers.
However, the direct target in cancer cells of its anticancer effect has
not been identified. The purpose of this study was to find the molecular
target of matrine to inhibit the proliferation of cancer cells and
explore its mechanism of action. Experimental Approach: The effect of
matrine on the proliferation of cancer cells were examined by MTT assay.
Pull-down assay and liquid chromatography-mass spectrometry/mass
spectrometry (LC-MS/MS) were performed to explore the target of matrine.
A series of in vitro and in vivo experiments were conducted to reveal
the mechanisms by which matrine targeted Src to regulate the downstream
signaling pathways of Src in cancer cells. Key Results: Herein we showed
that matrine inhibited the proliferation of cancer in vitro and in vivo.
Pull-down assay with matrine-amino coupling resins (MA beads) and
LC-MS/MS identified Src as the target of matrine. Src kinase domain is
required for its interaction with matrine and Ala392 in the kinase
domain participated in matrine-Src interaction. Intriguingly, matrine
was proven to inhibit Src kinase activity in a non-ATP-competitive
manner by blocking the autophosphorylation of Tyr419. Matrine
down-regulated the phosphorylation levels of MAPK/ERK, JAK2/STAT3 and
PI3K/Akt signaling pathways. Conclusions and Implications: Collectively,
matrine targeted Src, inhibited kinase activity and down-regulated its
downstream MAPK/ERK, JAK2/STAT3 and PI3K/Akt phosphorylation signaling
pathways to inhibit the proliferation of cancer cells.