BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation

Choi

Journal of Biological Chemistry

2014

Background:The mechanism by which oncogenic Ras contributes to epithelial-mesenchymal transition (EMT) is not clearly defined. Results:The "BLT2-ROS-NF-B"-linked cascade lies downstream of Ras and promotes EMT. Conclusion: Activation of leukotriene B 4 receptor-2 (BLT2)-linked pathway contributes to EMT in mammary epithelial cells. Significance: These findings suggest that BLT2 is a novel regulator of EMT in mammary epithelial cells.

Section: Methodsmentioning

confidence: 99%

Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells

Choi

Journal of Biological Chemistry

2014

“…RNA interference for BLT2, Nox1 and MMP-9 Scramble control and human BLT2-specific siRNA (for Rat2-BLT2 cells) were purchased from Ambion (Austin, TX, USA) using the following BLT2-target sequences as described previously (Hennig et al, 2008). Rat BLT2-specific siRNA (for Rat-2 and Rat2-HO6 cells) was purchased from Bioneer (Daejeon, Korea) and RNA interference for rat BLT2 and Nox1 was performed as described previously (Choi et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway

Seo

Cho

et al. 2009

Oncogene

Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B 4 receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-jB stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis.

Endocrine-Related Cancer

“…BLT2 is a receptor for leukotriene B4 and 12-HETE, and plays a critical role in tumor progression, as indicated by the finding that BLT2 is overexpressed in various cancers (Yoo et al 2004, Hennig et al 2008, Choi et al 2010. Recently, it has been reported that a BLT2-linked pathway evokes ROS production and up-regulates AR expression via the Nox4 pathway, while the Nox inhibitor, DPI, reduces AR expression (Lee et al 2012).…”

Section: Ar Overexpressionmentioning

confidence: 99%

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

Shiota

Yokomizo

Naito

2012

Oxidative stress caused by an increase in reactive oxygen species levels or a decrease in cellular antioxidant capacity can evoke the modulation of various cellular events including androgen receptor (AR) signaling via direct or indirect interactions. In this review, we summarize the mechanisms of AR activation by oxidative stress including: i) AR overexpression; ii) AR activation by AR co-regulators or intracellular signal transduction pathways; iii) generation of AR mutations or splice variants; and iv) de novo androgen synthesis. AR signaling augmented by oxidative stress appears to contribute to pro-survival and anti-apoptotic effects in prostate cancer cells in response to androgen deprivation therapy. In addition, AR signaling suppresses anti-survival and pro-apoptotic effects in prostate cancer cells in response to various cytotoxic and tumorsuppressive interventions including taxanes and radiation through the modulation of bIII-tubulin and ataxia telangiectasia-mutated kinase expression respectively. Taken together, AR signaling appears to render prostate cancer cells refractory to various therapeutic interventions including castration, taxanes, and radiation, indicating that AR signaling is a comprehensive resistant factor and crucial target for prostate cancer treatment.