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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.

Olfactomedin 4 suppresses prostate cancer cell growth and metastasis via negative interaction with cathepsin D and SDF-1