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Cell Death Dis. 2019 Oct 22;10(11):801. doi: 10.1038/s41419-019-2042-y.

EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells.

Author information

1
Department of Urology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
2
Atrin Pharmaceuticals, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA.
3
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, 60637, USA.
4
Department of Urology and Medical Social Sciences (DEV), Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
5
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
6
Division of Hematology, Department of Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
7
Department of Urology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. sarki.abdulkadir@northwestern.edu.
8
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. sarki.abdulkadir@northwestern.edu.

Abstract

The EPHB4 receptor is implicated in the development of several epithelial tumors and is a promising therapeutic target, including in prostate tumors in which EPHB4 is overexpressed and promotes tumorigenicity. Here, we show that high expression of EPHB4 correlated with poor survival in prostate cancer patients and EPHB4 inhibition induced cell death in both hormone sensitive and castration-resistant prostate cancer cells. EPHB4 inhibition reduced expression of the glucose transporter, GLUT3, impaired glucose uptake, and reduced cellular ATP levels. This was associated with the activation of endoplasmic reticulum stress and tumor cell death with features of immunogenic cell death (ICD), including phosphorylation of eIF2α, increased cell surface calreticulin levels, and release of HMGB1 and ATP. The changes in tumor cell metabolism after EPHB4 inhibition were associated with MYC downregulation, likely mediated by the SRC/p38 MAPK/4EBP1 signaling cascade, known to impair cap-dependent translation. Together, our study indicates a role for EPHB4 inhibition in the induction of immunogenic cell death with implication for prostate cancer therapy.

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