{Reference Type}: Journal Article
{Title}: Gentisic acid prevents colorectal cancer metastasis via blocking GPR81-mediated DEPDC5 degradation.
{Author}: Feng G;Zhang L;Bao W;Ni J;Wang Y;Huang Y;Lyv J;Cao X;Chen T;You K;Khan H;Shen X;
{Journal}: Phytomedicine
{Volume}: 129
{Issue}: 0
{Year}: 2024 Jul 10
{Factor}: 6.656
{DOI}: 10.1016/j.phymed.2024.155615
{Abstract}: <B>BACKGROUND: </B>Metastasis driven by epithelial-mesenchymal transition (EMT) remains a significant contributor to the poor prognosis of colorectal cancer (CRC), and requires more effective interventions. GPR81 signaling has been linked to tumor metastasis, while lacks an efficient specific inhibitor.<BR><B>OBJECTIVE: </B>Our study aimed to investigate the effect and mechanism of Gentisic acid on colorectal cancer (CRC) metastasis.<BR><B>METHODS: </B>A lung metastasis mouse model induced by tail vein injection and a subcutaneous graft tumor model were used. Gentisic acid (GA) was administered by an intraperitoneal injection. HCT116 was treated with lactate to establish an in vitro model.<BR><B>METHODS: </B>MC38 cells with mCherry fluorescent protein were injected into tail vein to investigate lung metastasis ability in vivo. GA was administered by intraperitoneal injection for 3 weeks. The therapeutic effect was evaluated by survival rates, histochemical analysis, RT-qPCR and live imaging. The mechanism was explored using small interfering RNA (siRNA), Western blotting, RT-qPCR and immunofluorescence.<BR><B>RESULTS: </B>GA had a therapeutic effect on CRC metastasis and improved survival rates and pathological changes in dose-dependent manner. GA emerged as an GPR81 inhibitor, effectively suppressed EMT and mTOR signaling in CRC induced by lactate both in vivo and in vitro. Mechanistically, GA halted lactate-induce degradation of DEPDC5 through impeding the activation of Chaperone-mediated autophagy (CMA).<BR><B>CONCLUSIONS: </B>CMA-mediated DEPDC5 degradation is crucial for lactate/GPR81-induced CRC metastasis, and GA may be a promising candidate for metastasis by inhibiting GPR81 signaling.