The role of PTEN in prostate cancer cell tropism to the bone micro-environment.
Little is known about the role of the tumor suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in prostate cancer bone metastasis. To explore this, we used a pTetOn PTEN cell line in which PTEN expression was reconstituted in a PTEN-null bone metastatic human prostate cancer cell line, LnCaP-C4-2. We found that C4-2 cells selectively migrated toward conditioned medium from primary mouse calvaria cells compared with that derived from lung fibroblasts. Further evaluation with conditioned medium from an established mouse calvaria osteoblast cell line and control non-osteoblast cell line indicates that osteoblastic characteristics convey this specific migration to C4-2 cells. We evaluated promiscuously metastatic PC-3 prostate as well as T24T and UMUC-3 bladder cells and found they did not have a specific migratory response to calvaria-conditioned medium as did C4-2. Induction of PTEN expression inhibited the motility of C4-2 cells toward calvaria-conditioned medium but had no effect on migration toward lung-conditioned medium and this inhibitory effect was dependent on the PTEN lipid phosphatase activity. Calvaria- but not lung-conditioned medium induced activation of the small GTPase Rac1. Constitutively active Rac1 but not focal adhesion kinase or Cdc42 could rescue cells from the inhibitory effect of PTEN on cell migration and PTEN induction was observed to inhibit Rac1 activation in response to calvaria-conditioned medium. Our results support the notion that loss of PTEN function in human prostate cancer may specifically facilitate bone rather than other organ metastasis and suggest that Rac1, as a PTEN effector, may contribute to this metastatic tropism.
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Department of Molecular Physiology and Biological Physics, Box 422, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
McRoberts
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Theodorescu
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D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D002633:Chemotaxis; D017077:Culture Media, Conditioned; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000166:cytology; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase / Q000378:metabolism / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012886:Skull / Q000166:cytology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D017077:Culture Media, Conditioned; C107953:RAC1 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein