Extracellular Vesicles in the Adaptive Process of Prostate Cancer during Inhibition of Androgen Receptor Signaling by Enzalutamide

Abstract

Current treatments for advanced prostate cancer focus on inhibition of the androgen receptor (AR) by androgen deprivation therapy (ADT). However, complex interactions mediated by tumor suppressors, oncogenes, aberrations of AR expression, or de novo androgen production have been shown to induce the adaptive response of prostate cancer, leading to the development of castration resistant prostate cancer. In this study, we report the effects of AR antagonist, enzalutamide on the protein contents of extracellular vesicles (EVs). EVs mediate cell-to-cell communication and increasing evidence shows the role of EVs in promoting cancer survival and metastasis. We found that treatment with enzalutamide alters the secretion of EVs, one of which is a plasma membrane calcium pump, ATP2B1/PMCA ATPase, as an AR-regulated EV protein. We highlight the networks of interactions between AR, Ca , and ATP2B1, where the extracellular proteins thrombospondin-1, gelsolin, and integrinß1 were previously reported as regulators for cancer progression and metastasis, indicating the potential role of EV-derived proteins in mediating calcium homoeostasis under AR inhibition by enzalutamide. Our data further highlight the cross-talk between AR signaling and EV pathways in mediating resistance toward ADT.

Extracellular Vesicles in Prostate Cancer Carcinogenesis, Diagnosis, and Management

“…Soekmadji et al recently demonstrated that exposure of LNCaP and DUCaP to dihydrotestosterone (DHT) increased the secretion of CD9-expressing exosomes (without any increase in the total number of secreted exosomes) ( 137 ). Proteomic analyses showed that DHT treatment, culture in androgen-free medium and treatment with the antiandrogen enzalutamide are effectively able to modify exosomes contents ( 137 , 138 ). When CD9-enriched exosomes obtained after DHT treatment were inserted in the culture media of androgen-deprived LNCaP cells, an increased proliferation was observed.…”

Role of Calcium Signaling in Prostate Cancer Progression: Effects on Cancer Hallmarks and Bone Metastatic Mechanisms

“…Plasma membrane Ca 2+ -ATPases (PMCAs) are calcium pumps that use ATP hydrolysis to push calcium from the cytosol into the extracellular milieu. PMCA1 has been identified as a protein that is regulated by the AR in PCa LNCaP cells [103]. Increased secretion of PMCA1 in extracellular vesicles has been associated with inhibition of the AR by the AR antagonist enzalutamide [103].…”

Monitoring Therapy Efficiency in Cancer through Extracellular Vesicles

“…For advanced PCa, current treatments focus on inhibition of the androgen receptor. Soekmadji et al [38] (Table 1) investigated EV's protein cargo in supernatant of prostate cancer cells after incubation with enzalutamide. The 34 vesicular proteins were described altered by the androgen receptor antagonist.…”

“…The 34 vesicular proteins were described altered by the androgen receptor antagonist. Especially the plasma membrane calcium pump, ATP2B1/PMCA ATPase, was identified as a part of the cross-talk of androgen receptor signaling and EV pathways in mediating resistance towards hormone therapy [38].…”