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Perillyl alcohol and rapamycin‐mediated inhibition of migration and invasion
Author(s) -
Sundin Tabetha,
Mollica Peter,
Peffley Dennis,
Hentosh Patricia
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.995.3
Subject(s) - du145 , pi3k/akt/mtor pathway , matrix metalloproteinase , angiogenesis , chemistry , cancer research , matrix metalloproteinase inhibitor , pharmacology , cell migration , cancer cell , cell culture , cancer , biology , cell , medicine , signal transduction , biochemistry , genetics , lncap
The plant‐derived isoprenoid perillyl alcohol (POH) exerts anti‐cancer properties via effects on mTOR (mechanistic target of rapamycin) signaling in a similar but distinct process as does rapamycin, a well‐studied mTOR inhibitor. Previously, rapamycin was shown to inhibit both matrix metalloproteinases (MMPs)‐2 and ‐9 in a human umbilical vein endothelial cell line. MMPs are key indicators of both angiogenesis induction and tumor cell metastatic activity. We evaluated clinically relevant concentrations of POH and rapamycin for their respective abilities to limit cellular migration and invasion of a highly metastatic human prostate cancer line–DU145. In a wound healing assay, POH or rapamycin significantly prevented DU145 cells from migrating into the wound area during a 24 hr period. Further, both agents inhibited DU145 movement through an ECM layer in a cell invasion assay. Gelatin zymography revealed that POH and rapamycin reduced the activity of secreted MMP‐2 and ‐9 in a time‐dependent manner. Additionally, decreased intracellular MMP‐2 activity was observed after treatment with either agent. Pre‐treatment with the proteasome inhibitor MG‐132 rescued MMP‐2 activity indicating that POH and rapamycin provoke MMP‐2 degradation. Our results establish comparable anti‐invasive abilities of POH–which displays fewer side effects–and rapamycin that are associated with MMP‐2 and ‐9 down‐regulation. Funding provided by a Golden Key Research Grant.