Dual Inhibition of Plasminogen Kringle 5 on Angiogenesis and Chemotaxis Suppresses Tumor Metastasis by Targeting HIF-1α Pathway

Wei-Bin Cai,Zu-Min Xu,Rui Cheng,Yang Zhang,Guo-Quan Gao,Chun-Kui Shao,Jian-Xing Ma,Xia Yang,Shu-Huan Fang,Zheng Wang,Zhong-Han Yang,Anjali Jain

doi:10.1371/journal.pone.0053152

Abstract

We had demonstrated that plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibited retinal neovascularization and hepatocellular carcinoma growth by anti-angiogenesis. The current study investigated the effects and the underlying mechanisms of K5 on both tumor growth and spontaneous pulmonary metastasis in Lewis lung carcinoma (LLC) implanted mouse model. Similarly, K5 could decrease expression of VEGF in LLC cells and grafted tissues and suppress tumor angiogenesis and growth. K5 had no direct effect on proliferation and apoptosis of LLC. However, K5 could significantly inhibit SDF-1α-induced chemotaxis movement of LLC cells and resulted in a great reduction of surface metastatic nodules and micrometastases in the lungs of LLC tumor-bearing mice. K5 also decreased expression of chemokine (C-X-C motif) receptor 4 (CXCR4) in LLC cells and grafted tissues. Furthermore, K5 down-regulated SDF-1α expression in metastatic lung tissues of LLC-bearing mice. Therefore, K5 may suppress tumor pulmonary metastasis through inhibiting SDF-1α-CXCR4 chemotaxis movement and down-regulation of VEGF. Moreover, the role of hypoxia inducible factor-1α (HIF-1α), a crucial transcriptional factor for both VEGF and CXCR4 expression, was evaluated. The siRNA of HIF-1α attenuated expression of VEGF and CXCR4 and inhibited LLC migration. K5 decreased HIF-1α protein level and impaired nuclear HIF-1α accumulation. These results showed for the first time that K5 inhibits LLC growth and metastasis via the dual effects of anti-angiogenesis and suppression of tumor cell motility by targeting the pivotal molecule, HIF-1α.

Highlights

Tumor angiogenesis is a prerequisite for malignantly transformed cells to grow and metastasize and constitutes an important point in the control of cancer progression [1]
As VEGF derived from tumor cells is the critical one of growth factors enhancing tumor microvessel density and inducing angiogenesis, we evaluated the effect of kringle 5 (K5) on the expression of VEGF in Lewis lung carcinoma (LLC) cells and tissues
Our results showed for the first time that K5 inhibits both tumor growth and metastasis in LLC via the dual effects of anti-angiogenesis and suppression of tumor cell motility by targeting hypoxia-inducible factor 1a (HIF-1a) pathway

Summary

Introduction

Tumor angiogenesis is a prerequisite for malignantly transformed cells to grow and metastasize and constitutes an important point in the control of cancer progression [1]. The hypoxic response is mediated through the transcription factors, hypoxia-inducible factor 1a (HIF-1a) [4]. Both clinical and experimental studies have revealed a significant association between the expression of HIF-1a and development and prognosis of malignant tumors [5]. HIF-1a signal pathways leading to the tumor angiogenesis and invasive migration have been suggested to be key steps of tumor metastatic progression [2,4]. It was hypothesized that inhibition of HIF-1a signal pathway would offer an innovative strategy for antiangiogenesis and anti-metastasis in cancer therapy [3]

Methods

Results

Conclusion