Metastatic and
castration-resistant disease is a fatal manifestation of
prostate cancer (PCa). The mechanism through which resistance to
androgen deprivation in PCa is developed remains largely unknown. Our understanding of the tumor microenvironment (TME) and key signaling pathways between
tumors and their TME is currently changing in light of the generation of new knowledge with regard to
cancer progression. A
disintegrin and
metalloproteinase domain-containing
protein 9 (ADAM9) is a membranous bridge forming cell-cell and cell-matrix connections that regulate
tumor aggressiveness and
metastasis. However, it is not known whether ADAM9 expressed in the TME contributes to the CRPC phenotype. In this study, we aimed to investigate the expression patterns of ADAM9 in
prostate cancer-associated fibroblasts (CAFs). We also intended to elucidate the effects of both stromal cell- and
cancer cell-derived ADAM9 on the progression of CRPC and the implicated molecular pathways. By using both clinical specimens and cell lines, we herein showed that unlike the membrane anchored ADAM9 overexpressed by both PCa cells and prostate CAFs, the secreted
isoform of ADAM9 (sADAM9) was strongly detected in CAFs, but rarely in
tumor cells, and that could be a
serum marker for PCa patients. We demonstrated that functionally sADAM9 are characterized as
chemoattractant for the directed movement of
androgen-independent PCa cells through
integrin downstream FAK/AKT pathway, supporting that elevated sADAM9 by prostate CAFs could be responsible for the promotion of CRPC
metastasis. Moreover, by stimulating PCa cells with sADAM9, we found that ubinuclein-2 (UBN2) expression was increased. A positive correlation of ADAM9 and UBN2 expression was observed in
androgen receptor-expressing PCa cell lines and further confirmed in clinical PCa specimens. Using a genetic modification approach, we identified UBN2 as a downstream target gene of ADAM9 that is critical for the survival of
androgen-dependent PCa cells in response to
androgen deprivation, through the induction and effect of the
aldo-keto reductase family 1 member C3 (AKR1C3). Collectively, our results reveal a novel action of ADAM9 on the transition of
androgen-dependent PCa cells into an
androgen-independent manner through the UBN2/AKR1C3 axis; the aforementioned action could contribute to the clinically-observed acquired
androgen-deprivation
therapy resistance.