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.
Highlights
Prostate cancer (PC) is the most common cancer in men worldwide
These results indicate that EPHB4 is a valuable prognostic biomarker and raises the hypothesis that it could be a therapeutic target in prostate cancer patients
We describe for the first time to our knowledge that targeting EPHB4 induces immunogenic cell death (ICD) associated with endoplasmic reticulum (ER) stress, decreased glucose transporter and glucose uptake
Summary
Prostate cancer (PC) is the most common cancer in men worldwide. While therapy targeted at the androgen receptor pathway shows initial efficacy, a majority of patients with advanced PC go on to develop resistance[2,3,4]. There is a need for novel therapies that target additional pathways important for the growth and survival of prostate cancer cells. Tyrosine kinase inhibitors (TKIs) are being investigated as an additional strategy to treat prostate cancer[5,6,7,8]. Receptor tyrosine kinases (RTKs) regulate of cell proliferation, migration, apoptosis, and survival, and plays a role in the progression and development of multiple cancers[9,10].
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