The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region

Abstract

Leukotriene B4 (LTB4) is a potent pro-inflammatory eicosanoid that is derived from arachidonic acid, and its signaling is known to have a tumor-promoting role in several cancer types. In this study, we investigated whether enhanced LTB4 signaling confers resistance to the cytostatic transforming growth factor-β1 (TGF-β1) response. We found that LTB4 pretreatment or ectopic expression of BLT1, a high affinity LTB4 receptor, fully abrogated TGF-β1-induced cell cycle arrest and expression of p15INK4B and p27KIP1. Mechanism study revealed that LTB4-mediated suppression of TGF-β1-induced Smad3 activation and growth inhibition was due to enhanced phosphorylation of Smad3 linker region (pSmad3L) through activation of BLT1-NAD(P)H oxidase (NOX)-reactive oxygen species (ROS)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3-K)-extracellular signal-activated kinase1/2 (ERK1/2)-linked signaling cascade. Furthermore, the LTB4/BLT1 signaling pathway leading to pSmad3L was constitutively activated in breast cancer cells and was correlated with TGF-β1-resistant growth of the cells in vitro and in vivo. In human breast cancer tissues, the expression level of pSmad3L (Thr179) had a positive correlation with BLT1 expression. Collectively, our data demonstrate for the first time that the induction of pSmad3L through BLT1-NOX-ROS-EGFR-PI3K-ERK1/2 signaling pathway is a key mechanism by which LTB4 blocks the anti-proliferative responses of TGF-β1, providing a novel mechanistic insight into the connection between enhanced inflammatory signal and cancer cell growth.

Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4

“…Ihara and colleagues demonstrated the involvement of the BLT1 pathway in colon cancer cell proliferation (45). Furthermore, the LTB 4 -BLT1 axis could block TGF-b-induced cell growth inhibition (46). In contrast, some studies have indicated the crucial roles of BLT2 in LTB 4 -mediated cancer cell proliferation (15), invasiveness (38), and the epithelial-mesenchymal transition (40,41).…”

Genomic Expression in Peripheral Blood Mononuclear Cells (Pbmcs) of Patients with Hepatocellular Carcinoma (Hcc): Effect of Ablative Treatment

“…The LTB4R gene codes for the Leukotriene B4 receptor, a pro-in ammatory eicosanoid derived from arachidonic acid, which acts as a chemoattractant for phagocytes. It is precociously up-regulated in many tumors (ovary, breast, liver, esophagus, colon), where it acts as an oncogene through various mechanisms: for example, it negatively regulates the anti-proliferative action of TGF-β1 in breast carcinoma [47] and mediates proliferation induced by the oncogenic protein X of hepatitis B virus (HBx) in HBV-mediated HCC [48]. Because its upregulation correlates with a worse outcome, it has been shown to be a valid prognostic marker and a possible therapeutic target.…”

The yin and yang of leukotriene B 4 mediated inflammation in cancer

“…Jeon et al have shown that Leukotriene B 4 signaling in cancer cells confers resistance to transforming growth factor-β1 (TGF-β1)-induced cytostatic response through pSmad3L activation [57]. This was further validated by a positive correlation of BLT1 expression to pSmad3L expression in human breast cancer tissues.…”