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

Vinay Sagar, Rajita Vatapalli, Barbara Lysy, Sahithi Pamarthy, Jonathan F. Anker, Yara Rodriguez, Huiying Han, Kenji Unno, Walter M. Stadler, William J. Catalona, Maha Hussain, Parkash S. Gill, Sarki A. Abdulkadir*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article number801
JournalCell Death and Disease
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2019

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Sagar, V., Vatapalli, R., Lysy, B., Pamarthy, S., Anker, J. F., Rodriguez, Y., Han, H., Unno, K., Stadler, W. M., Catalona, W. J., Hussain, M., Gill, P. S., & Abdulkadir, S. A. (2019). EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells. Cell Death and Disease, 10(11), [801]. https://doi.org/10.1038/s41419-019-2042-y