Fatty acid binding protein 4 enhances prostate cancer progression by upregulating matrix metalloproteinases and stromal cell cytokine production.

Mingguo Huang,Mitsuru Saito,Takehiko Sasaki,Hiroshi Tsuruta,Hiroshi Nanjo,Tomonori Habuchi,Shigeru Satoh,Atsushi Koizumi,Kazuyuki Numakura,Takamitsu Inoue,Shintaro Narita

doi:10.18632/oncotarget.22908

Mingguo Huang, Mitsuru Saito + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.22908

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Journal: Oncotarget	Publication Date: Dec 4, 2017
Citations: 34	License type: cc-by

Affiliation: Akita University

Abstract

Fatty acid binding protein 4 (FABP4) is an abundant protein in adipocytes, and its production is influenced by high-fat diet (HFD) or obesity. The prostate stromal microenvironment induces proinflammatory cytokine production, which is key for the development and progression of prostate cancer (PCa). Here, we show that high FABP4 expression and its secretion by PCa cells directly stimulated PCa cell invasiveness by upregulating matrix metalloproteinases through phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways. In addition, prostate stromal cells augmented PCa cell invasiveness by secreting interleukin-8 and -6 in response to FABP4. This was abrogated by the FABP4 specific inhibitor, BMS309403. Furthermore, a mouse xenograft experiment showed HFD enhanced PCa metastasis and invasiveness by the upregulation of FABP4 and interleukin-8. Clinically, the serum level of FABP4 was significantly associated with an aggressive type of PCa rather than obesity. Taken together, FABP4 may enhance PCa progression and invasiveness by upregulating matrix metalloproteinases and cytokine production in the PCa stromal microenvironment, especially under HFD or obesity.

Highlights

Prostate cancer (PCa) is one of the most commonly diagnosed and leading causes of cancer-related death in Western countries and Japan [1,2,3]
To address the functional role of Fatty acid binding protein 4 (FABP4) secreted by PC-3 cells in the prostate cancer (PCa) stroma, prostate stromal cells (PrSC) were treated with recombinant FABP4 or PC-3 conditioned medium (CM), and secreted cytokines were measured by a Human cytokine array for Interleukin (IL)8, IL-1β, IL-6, IL-10, TNFα, and IL-12p70
The expression of alpha smooth muscle actin, a stromal activation marker, was upregulated by treatment with 100 ng ml-1 recombinant FABP4 (rFABP4) or PC-3 CM (2.7- and 2.1-fold, respectively), and the effects were blocked by adding 30 μM BMS309403 (1.0- and 0.9-fold, respectively) (Figure 1D). Some of these data were not evaluated by statistical analysis, the results suggest that FABP4 secreted by some PCa cells may stimulate surrounding prostate stromal cells to produce proinflammatory cytokines in the prostate stromal tumor microenvironment

Summary

Introduction

Prostate cancer (PCa) is one of the most commonly diagnosed and leading causes of cancer-related death in Western countries and Japan [1,2,3]. Many epidemiological studies suggest that the risk of PCa is increasingly associated with environmental factors such as highfat diet (HFD) and obesity [4,5,6]. The prostate stromal microenvironment has emerged as a key factor in the growth and development of PCa [12]. Prostate stromal fibroblasts are a common component of the prostate stroma, and crosstalk with adjacent cancer cells might influence tumor progression by the secretion of proinflammatory cytokines and growth factors [13, 14]. Recent studies have shown that periprostatic inflammation induced by HFD and obesity was strongly associated with the progression of various cancers including PCa [15, 16]

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