Tumoristatic effects of endostatin in prostate cancer is dependent on androgen receptor status

Abstract

Background Although antiangiogenic therapy is a promising new line of therapy for prostate cancer, we recently reported that stable expression of endostatin arrested the progression of prostate cancer to poorly differentiated state and distant metastasis in TRAMP mice. However, the same therapy failed to provide any benefit when given either during or after the onset of metastatic switch. The present study determined the possible mechanisms behind the selective advantage of endostatin therapy in early stage disease. Methods Angiogenesis-related gene expression analysis was performed to identify target genes and molecular pathways involved in the therapy effects. Based on the results from in vivo studies, and recapitulation of the in vivo data in vitro using tumorigenic and non-tumorigenic human prostate cancer cells that are either androgen-sensitive or androgen-independent, analyses of possible mechanisms of the selective advantage of early treatment were performed using assays for cell proliferation, apoptosis, migration and cell signaling. The identified mechanisms were further confirmed in vivo. Results Results indicated that cells with high androgen receptor (AR) expression were more sensitive to endostatin treatment than androgen-independent cells with low or no AR expression. Endostatin was found to significantly downregulate the expression of growth factors, receptor tyrosine kinases, proteases, and AR both in vitro and in vivo only when the cells express high levels of AR. Cell proliferation was not influenced by endostatin treatment but migration was significantly affected only in androgen-sensitive cells. Targeted downregulation of AR prior to endostatin treatment in androgen sensitive cells and overexpression of AR in androgen independent cells indicated that the effect of endostatin via AR downregulation is mediated by a non-genotropic mechanism on Ras and RhoA pathways, and independently of AR on MAPK/ERK pathway. Conclusions These data indicate that systemically stable endostatin expression delays the onset of metastatic switch by acting on multiple pathways involving AR.

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

“…Like other endogenous antiangiogenic factors, ES is known to induce apoptosis of endothelial cells through binding to and functionally disrupting cell-surface receptors (i.e., integrins) (26,27). In line with our previous study (28), ES treatment also induced apoptosis in LNCaP cells by showing the activation of caspase-3 (Fig. S2D).…”

KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer

“…Although we have not yet performed functional experiments to examine the possibility that our approach will provide targets for therapy for advanced prostate cancer, we have identified many genes that are inversely regulated by Klf4 and that overlap with genes expressed in human malignant tumors. Potential candidate genes could be Efna3 (a receptor kinase ligand) and Tpx2, which are overexpressed in aggressive prostate cancer ( Isayeva et al, 2009 ; Wang et al, 2009 ) and predict poor prognosis in colon and gastric cancers ( Tomii et al, 2017 ; Wei et al, 2013 ) in addition to BGN and ALDH7A1, whose overexpression is associated with a poor prognosis in prostate ( Jacobsen et al, 2017 ; van den Hoogen et al, 2011 ).…”

Prostatic angiogenic responses in late life: Antiangiogenic therapy influences and relation with the glandular microenvironment in the transgenic adenocarcinoma of mouse prostate (TRAMP) model

“…To date, there is no evidence in literature about a direct action of SU5416 and TNP‐470 on the endogenous expression of endostatin. According to Isayeva et al , prostatic cells with high AR expression were more sensitive to long‐term treatment with endostatin, indicating the ability of this molecule to delay metastasis in TRAMP mice by means of its action on multiple pathways involving AR. At the same time, it is known that TNP‐470 is capable of upregulating the androgen receptor gene expression, leading to increased AR protein levels in the intracellular environment .…”