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 5

Hypoxia induces tumor cells to secrete IL-8.

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Hypoxia induces tumor cells to secrete IL-8. (A and B) Western blot (A) ...
(A and B) Western blot (A) and qPCR (B) analysis of IL-8 in B16F10 and LLC cells after treatment with normoxia or hypoxia for 24 hours (n = 3). (C and D) Western blot (C) and qPCR (D) analysis of IL-8 in B16F10 and LLC cells after treatment with Ctrl-R or JP1 (50 μM) for 24 hours in normoxic or hypoxic condition (n = 3). (E) Schematic representation of the B16F10 cell allografts for Ctrl-R (50 mg/kg/day) or JP1 (50 mg/kg/day) treatment in the normoxic or hypoxic condition (n = 6). (F and G) The tumor growth curves and tumor/body weight (%) in indicated groups. (H) Quantitation of the mice that developed lung metastases after surgical removal of the primary B16F10 tumors with indicated treatments (n = 6). (I and J) Representative immunohistochemical staining of HIF1α in the B16F10 tumor nodules in indicated groups (I) and quantification of HIF1α intensity (J) (n = 6). Scale bars: 50 μm. (K and L) Quantitation of HIF1α (K) and IL-8 (L) protein extracted from B16F10 tumor nodules in indicated groups by Western blot (n = 3). (M–O) Representative fluorescence images of α-SMA (green), desmin (green), CD31 (red), and DAPI nuclear staining in indicated groups (M); quantitation of α-SMA (N) and desmin (O) coverage is shown (n = 6). Scale bars: 50 μm. *P < 0.05, **P < 0.01, ***P < 0.001 by ordinary 1-way ANOVA (B, D, G, J–L, N, and O).