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Cellular Oncology
Published in: Cellular Oncology 1/2021

Open Access 01-02-2021 | Raloxifene | Original Article

Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERβ and IL-6/gp130/STAT3 signaling

Authors: Ioannis Pozios, Nina N. Seel, Nina A. Hering, Lisa Hartmann, Verena Liu, Peter Camaj, Mario H. Müller, Lucas D. Lee, Christiane J. Bruns, Martin E. Kreis, Hendrik Seeliger

Published in: Cellular Oncology | Issue 1/2021

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Abstract

Purpose

Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERβ signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling.

Methods

Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERβ. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed.

Results

Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERβ, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene.

Conclusions

Inhibition of ERβ and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERβ signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERβ isotype.
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Metadata
Title
Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERβ and IL-6/gp130/STAT3 signaling
Authors
Ioannis Pozios
Nina N. Seel
Nina A. Hering
Lisa Hartmann
Verena Liu
Peter Camaj
Mario H. Müller
Lucas D. Lee
Christiane J. Bruns
Martin E. Kreis
Hendrik Seeliger
Publication date
01-02-2021
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 1/2021
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-020-00559-9

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