Abstract : Perlecan (Pln), the major heparan sulfate proteoglycan (HSPG) in the bone marrow stromal ECM functions as a permissive ECM molecule, or co-receptor, that delivers HBGF's to high affinity receptors. Heparan sulfate chains on Pln are located in a unique N-terminal domain I (PlnDI) which functions as the co-receptor for HBGFs. Our purpose is to study the functions of Pln in prostate cancer cell survival, proliferation and apoptosis. We hypothesize that Pln, acting through PlnDI, delivers HBGFs to the cancer cell surface, promotes proliferation, cell survival and protects them from apoptosis. The Pln knockdown studies showed that Pln knockdown clones grow poorly compared to the parental or control transfected C4-2B cells. PlnDI failed to rescue the poorly proliferation. Western blot of Akt/MAPK pathway of these knockdown clones showed that Pln is not a major regulator in these pathways. We used three different prostate cancer cell lines: LnCaP, its derivative, C4-2B, and PC3 as model systems to study the protection function of PlnDI. We harvested conditioned medium from bone stromal cell lines, HS27a and HS5, which produce abundant Pln. The proteoglycan rich fraction containing Pln was obtained using anion exchange bead chromatography, then tested as a survival factor for the three different prostate cancer cell lines. DNA fragmentation experiments showed that bone stromal derived Pln from conditioned medium protected all three lines of prostate cancer cells from camptothecin induced apoptosis. We also supplied purified, fully glycosylated recombinant PlnDI protein to prostate cancer cells, which also protected cells from apoptosis. The Pln knockdown cell are also more susceptible in response to the apoptosis inducers anti-Fas and camptothecin, and that exogenous PlnDI can rescue survival. Taken together, these studies demonstrate that Pln present in the bone marrow compartment can promote cell proliferation.