Universität zu Köln

Pozios, Ioannis, Seel, Nina N., Hering, Nina A., Hartmann, Lisa, Liu, Verena, Camaj, Peter, Mueller, Mario H., Lee, Lucas D., Bruns, Christiane J., Kreis, Martin E. and Seeliger, Hendrik . Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ER beta and IL-6/gp130/STAT3 signaling. Cell. Oncol.. DORDRECHT: SPRINGER. ISSN 2211-3436

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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 ER beta 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 ER beta 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 ER alpha and ER beta. 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 ER beta, but not of ER alpha, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3(Y705)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 ER beta 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 ER beta 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 ER beta isotype.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pozios, Ioannis UNSPECIFIED UNSPECIFIED UNSPECIFIED Seel, Nina N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hering, Nina A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Camaj, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Mario H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Lucas D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Christiane J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kreis, Martin E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeliger, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-318949
DOI:	10.1007/s13402-020-00559-9
Journal or Publication Title:	Cell. Oncol.
Publisher:	SPRINGER
Place of Publication:	DORDRECHT
ISSN:	2211-3436
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ESTROGEN-RECEPTOR-BETA; MESSENGER-RNA EXPRESSION; CANCER-CELLS; BREAST-CANCER; TAMOXIFEN; INTERLEUKIN-6; ALPHA; LIVER; PROLIFERATION; ANGIOGENESIS Multiple languages Oncology; Cell Biology; Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31894