The human
olfactomedin 4 gene (OLFM4) encodes an
olfactomedin-related
glycoprotein. OLFM4 is normally expressed in a limited number of tissues, including the prostate, but its
biological functions in prostate are largely unknown. In this study, we found that OLFM4
messenger RNA was reduced or undetectable in
prostate cancer tissues and
prostate cancer cell lines. To study the effects of OLFM4 on
prostate cancer progression, we transfected PC-3
prostate cancer cells with OLFM4 to establish OLFM4-expressing PC-3 cell clones. The OLFM4-expressing PC-3 cell clones were found to have decreased proliferation and invasiveness compared with vector-transfected control PC-3 cells in vitro. In addition, nude mice injected with OLFM4-expressing PC-3 cells demonstrated reduced
tumor growth and bone invasion and
metastasis compared with mice injected with vector-transfected control cells. Mechanistic studies revealed that OLFM4 may exhibit its anticancer effects through regulating cell autophagy by targeting
cathepsin D, as OLFM4 reduced
cathepsin D protein levels and enzymatic activity and attenuated
cathepsin D-induced
cancer cell proliferation. In addition, overexpression of OLFM4 abrogated stromal cell derived factor-1 (SDF-1)-induced PC-3 cell invasiveness in a
Matrigel invasion assay, partially through blocking SDF-1-mediated AKT phosphorylation. Coimmunoprecipitation and immunofluorescence staining studies in OLFM4-expressing PC-3 cells demonstrated a direct interaction between OLFM4 and
cathepsin D or SDF-1. Taken together, these results suggest that OLFM4 negatively interacts with
cathepsin D and SDF-1 and inhibits
prostate cancer growth and bone
metastasis.