Macrophage migration inhibitory factor (MIF), a proinflammatory
cytokine, is overexpressed in
prostate cancer, but the mechanism by which MIF exerts effects on
tumor cells remains undetermined. MIF interacts with its identified membrane receptor, CD74, in association with CD44, resulting in ERK 1/2 activation. Therefore, we hypothesized that increased expression or surface localization of CD74 and MIF overexpression by
prostate cancer cells regulated
tumor cell viability.
Prostate cancer cell lines (LNCaP and DU-145) had increased MIF gene expression and
protein levels compared with normal human prostate or benign prostate epithelial cells (p < 0.01). Although MIF, CD74, and CD44 variant 9 expression were increased in both
androgen-dependent (LNCaP) and
androgen-independent (DU-145)
prostate cancer cells, cell surface of CD74 was only detected in
androgen-independent (DU-145)
prostate cancer cells. Therefore, treatments aimed at blocking CD74 and/or MIF (e.g., inhibition of MIF or CD74 expression by RNA interference or treatment with anti-MIF- or anti-CD74- neutralizing Abs or MIF-specific inhibitor, ISO-1) were only effective in
androgen-independent
prostate cancer cells (DU-145), resulting in decreased cell proliferation, MIF
protein secretion, and invasion. In DU-145 xenografts, ISO-1 significantly decreased
tumor volume and
tumor angiogenesis. Our results showed greater cell surface CD74 in DU-145
prostate cancer cells that bind to MIF and, thus, mediate MIF-activated signal transduction. DU-145
prostate cancer cell growth and invasion required MIF activated signal transduction pathways that were not necessary for growth or viability of
androgen-dependent prostate cells. Thus, blocking MIF either at the
ligand (MIF) or receptor (CD74) may provide new, targeted specific
therapies for
androgen-independent
prostate cancer.