JP1 normalizes tumor vasculature to suppress metastasis and facilitate drug delivery by inhibiting IL-8
Jiahua Cui, Zhen Che, Lu Zou, Dongyin Chen, Zhan Xie, Kun Ding, Huning Jiang, Aiping Li, Jianwei Zhou, Yongqian Shu
Jiahua Cui, Zhen Che, Lu Zou, Dongyin Chen, Zhan Xie, Kun Ding, Huning Jiang, Aiping Li, Jianwei Zhou, Yongqian Shu
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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

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Figure 3

JP1 promotes tumor vascular normalization by inhibiting IL-8.

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JP1 promotes tumor vascular normalization by inhibiting IL-8. (A) Volcan...
(A) Volcano plot of 60 genes involved in tumor vascular normalization among Ctrl-R– or JP1-treated (50 μM for 48 hours) B16F10 cells (n = 3). (B) Heatmap of 12 significantly downregulated proteins after JP1 treatment (n = 3). (C and D) Quantitation of IL-8 protein after JP1 treatment with indicated concentrations for 48 hours in B16F10 (C) and LLC (D) cells (n = 3). (E and F) IL-8 protein extracted from B16F10 (E) and LLC (F) tumor nodules was assessed by Western blot; quantitation of IL-8 protein concentrations is shown (n = 6). (G) Representative immunofluorescent staining of α-SMA (green) and IL-8 (red) in human mole and melanoma. Scale bars: 200 μm. The dashed box is further magnified by 74×. (H and I) quantitation of IL-8+ area (H) and α-SMA+ area (I) between mole and melanoma. (J) Schematic representation of the B16F10 (IL8WT) and B16F10 (IL8KO) cell allografts for Ctrl-R (50 mg/kg/day) or JP1 (50 mg/kg/day) treatment (n = 6). (K and L) The tumor growth curves and tumor/body weight (%) in indicated groups. (M) Quantitation of the mice that developed lung metastases after surgical removal of the primary tumors with indicated treatments (n = 5). (N and O) Representative fluorescence images of α-SMA (green), CD31 (red), and DAPI nuclear staining in indicated groups (N) and quantitation of α-SMA coverage (O) (n = 6). Scale bars: 100 μm. (P and Q) Representative fluorescence images of desmin (green), CD31 (red), and DAPI nuclear staining in indicated groups (P) and quantitation of desmin coverage (Q) (n = 6). Scale bars: 100 μm. (R–T) The proteins extracted from B16F10 tumor nodules in indicated groups were assessed by Western blot (R); quantitation of α-SMA (S) and desmin (T) protein concentrations is shown (n = 3). (U) Quantitation of vascular permeability in indicated groups (n = 6). *P < 0.05; **P < 0.01; ***P < 0.001 by ordinary 1-way ANOVA (C, D, L, O, Q, and S–U) or unpaired, 2-tailed Student’s t test (E, F, H, and I).