JP1 normalizes tumor vasculature to suppress metastasis and facilitate drug delivery by inhibiting IL-8
Jiahua Cui, … , Jianwei Zhou, Yongqian Shu
Jiahua Cui, … , Jianwei Zhou, Yongqian Shu
Published May 16, 2023
Citation Information: JCI Insight. 2023;8(12):e161675. https://doi.org/10.1172/jci.insight.161675.
View: Text | PDF
Research Article Angiogenesis Oncology

JP1 normalizes tumor vasculature to suppress metastasis and facilitate drug delivery by inhibiting IL-8

Abstract

Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In this study, we report that the antitumor peptide JP1 regulated mitochondrial metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improved the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibited the secretion of IL-8 by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature resulted in mature and regular blood vessels, which made the tumor microenvironment form a benign feedback loop consisting of vascular normalization, sufficient perfusion, and an oxygen-rich microenvironment, prevented tumor cells from entering the vasculature, and inhibited metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel maintained a certain vascular density in the tumor and promoted tumor vascular normalization, increasing the delivery of oxygen and drugs and enhancing the antitumor effect. Collectively, our work highlights the antitumor peptide JP1 as an inhibitor of metastasis initiation and its mechanism of action.

Authors

Jiahua Cui, Zhen Che, Lu Zou, Dongyin Chen, Zhan Xie, Kun Ding, Huning Jiang, Aiping Li, Jianwei Zhou, Yongqian Shu

×

Figure 6

JP1 promotes intratumoral delivery of PTX and enhances the antitumor effect.

Options: View larger image (or click on image) Download as PowerPoint
JP1 promotes intratumoral delivery of PTX and enhances the antitumor eff...
(A) Schematic representation of the B16F10 cell allograft model. Both JP1 and PTX alone or in combination were administered by intraperitoneal injection in mice (n = 12). On day 10, six mice were injected with Evans blue to perform vessel permeability assays; 6 mice were injected with PTX to quantify intratumoral PTX concentration. (B and C) The tumor growth curves and tumor/body weight (%) in indicated groups. (D–G) Representative fluorescence images of α-SMA (green), desmin (green), CD31 (red), and DAPI nuclear staining in indicated groups (D); quantitation of α-SMA (E), desmin (F), and CD31 (G) coverage are shown (n = 6). Scale bar: 50 μm. (H–J) Representative immunohistochemical staining of HIF1α and IL-8 in the B16F10 tumor nodules in indicated groups (H). Quantification of HIF1α (I) and IL-8 (J) intensity (n = 6). Scale bars: 50 μm. (K) Quantitation of vascular permeability after solvent, JP1, PTX, and JP1 combined with PTX treatment (n = 5). (L) PTX standard solution exhibits a peak with a retention time of 15.922 minutes by HPLC analysis. (M) Quantitation of intratumoral PTX concentrations in indicated groups (n = 6). *P < 0.05; **P < 0.01; ***P < 0.001 by ordinary 1-way ANOVA (C, E–G, I–K, and M).