Oxoaporphine Pr(III) complex inhibits hepatocellular carcinoma progression and metastasis by disrupting tumor cell-macrophage crosstalk

Tumor cells and macrophages communicate through the secretion of various cytokines to jointly promote the malignant development of cancers. We synthesized and characterized an oxoaporphine Pr(III) complex (PrL3(NO3)(3)) and found that it inhibits hepatocellular carcinoma (HCC) progression and metastasis by disrupting HCC cell-macrophage crosstalk. PrL3(NO3)(3) treatment upregulated CD86, TNF-alpha, and IL-1 beta and downregulated CD163, CD206, CCL2, and VEGFA in macrophages. Our mRNA-Seq results demonstrated that PrL3(NO3)(3) inhibited macrophage M2-like polarization by inhibiting the AMPK pathway and activating the NF-kappa B pathway by upregulating RelA/p65 Ser536 phosphorylation. This kind of macrophage polarization significantly inhibited HCC cell proliferation, migration, and invasion. In addition, PrL3(NO3)(3) inhibited the migration, invasion, and chemotaxis of HCC cells by downregulating the expression of EMT-related markers and CCL2. hTFtarget database analysis revealed that PrL3(NO3)(3) inhibited NF-kappa B nuclear translocation by upregulating RelA/p65 Ser536 phosphorylation in HCC cells, thereby downregulating the expression of Snail and CCL2. HCC tissue microarray analysis revealed that downregulation of RelA/p65 Ser536 phosphorylation is a driving event in HCC malignant progression. In conclusion, PrL3(NO3)(3) effectively inhibits HCC cell-macrophage crosstalk by upregulating RelA/ p65 Ser536 phosphorylation. This is the first report of a lanthanide complex exerting regulatory effects on both tumors and tumor-associated macrophages, providing a new strategy for the development of effective antitumor drugs.

Automated summary

In this study, we synthesized and characterized a oxoaporphine Pr(III) complex that was found to inhibit the progression and metastasis of hepatocellular carcinoma (HCC) by disrupting the communication between HCC cells and macrophages. The complex upregulated certain molecules in macrophages and inhibited their polarization, which significantly inhibited HCC cell proliferation, migration, and invasion. Additionally, the complex inhibited the migration, invasion, and chemotaxis of HCC cells by downregulating the expression of certain markers. Overall, this is the first report of a lanthanide complex exerting regulatory effects on both tumors and tumor-associated macrophages, providing a new strategy for the development of effective antitumor drugs.