Oxoaporphine Pr(III) complex inhibits hepatocellular carcinoma progression and metastasis by disrupting tumor cell–macrophage crosstalk - 04/12/23
, Hong Liang ⁎ Abstract |
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 (PrL 3 (NO 3 ) 3 ) and found that it inhibits hepatocellular carcinoma (HCC) progression and metastasis by disrupting HCC cell–macrophage crosstalk. PrL 3 (NO 3 ) 3 treatment upregulated CD86, TNF-α, and IL-1β and downregulated CD163, CD206, CCL2, and VEGFA in macrophages. Our mRNA-Seq results demonstrated that PrL 3 (NO 3 ) 3 inhibited macrophage M2-like polarization by inhibiting the AMPK pathway and activating the NF-κB pathway by upregulating RelA/p65 Ser536 phosphorylation. This kind of macrophage polarization significantly inhibited HCC cell proliferation, migration, and invasion. In addition, PrL 3 (NO 3 ) 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 PrL 3 (NO 3 ) 3 inhibited NF-κB 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, PrL 3 (NO 3 ) 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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | PrL 3 (NO 3 ) 3 inhibited HCC progression by disrupting tumor cell–macrophage crosstalk. |
• | PrL 3 (NO 3 ) 3 prevented M2-like polarization of macrophages. |
• | PrL 3 (NO 3 ) 3 suppressed the migration, invasion, and chemotaxis of HCC cells. |
• | PrL 3 (NO 3 ) 3 promoted RelA/p65 Ser536 phosphorylation in HCC cells and macrophages. |
• | RelA/p65 Ser536 phosphorylation is an ideal druggable target for HCC. |
Abbreviations : HCC, AMPK, NF-κB, BMDM, IL-4, IL-13, IL-1β, TNF-α, VEGFA, CCL2, CCL3, CCL5, CXCL9, CXCL10, TAM, AICAR, BAY 11–7082, PMA, EMT, DEGs, CCK-8, CM, ChIP, HPLC, ELISA, RT-qPCR, FBS, mRNA-seq, p-p65 Ser536
Keywords : Oxoaporphine Pr(III) complex, HCC, NF-κB, AMPK, Macrophage polarization
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Vol 169
Article 115849- décembre 2023 Retour au numéro
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