The tumor suppressor gene PTEN is frequently inactivated in advanced human prostate cancer but little is known about its role in prostate cancer bone metastasis. To explore the role of PTEN in this process, we have reconstituted PTEN expression in a PTEN-null bone metastatic human prostate cancer cell line, LnCaP C4-2, using the Tet-On inducible system. In the Boyden chamber motility assay, we found that C4-2 cells selectively migrated towards condition media from primary mouse calvaria compared to that derived from lung fibroblasts, suggesting that specific factor(s) presented in bone condition media stimulated cancer cell migration. Similar stimulation of cell migration was observed with condition media from an established mouse calvaria osteoblast cell line, MC3T3 clone 4. In contrast, condition media from the non osteoblast clone 24 of MC3T3 cells had less effect on cell migration (p=0.047). C4-2 growth rates were similar in primary calvaria condition media vs lung condition media indicating the difference of cell motility towards calvaria condition media vs lung condition media is not due to their effect on cell growth. Expression of PTEN inhibited the motility of C4-2 cells towards calvaria conditioned but not lung conditioned media and this inhibitory effect was dependent on its lipid phosphatase activity. Furthermore, similar expression levels of constitutively active Rac1 but not Cdc42 could partially abolish this inhibitory effect suggesting the inhibitory effect of PTEN is mediated in part by this small GTPase. In summary, our results provide evidence that bone specific factor(s) promotes prostate cancer cell migration and potentially implicate PTEN in prostate cancer bone metastasis.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]