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Ibuprofen Inhibits Survival of Bladder Cancer Cells by Induced Expression of the p75^NTR Tumor Suppressor Protein

¹ Department of Cell Biology and ² Vincent T. Lombardi Cancer Center, Georgetown University Medical Center; and ³ Department of Urology, Georgetown University Hospital, Washington, D.C.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammation and as analgesics by inhibition of cyclooxygenase-2. At higher concentrations, some NSAIDs inhibit proliferation and induce apoptosis of cancer cells. Although several molecular mechanisms have been postulated to explain the anticancer effects of NSAIDs, they do not involve merely the inhibition of cyclooxygenase-2, and a more proximate initiator molecule may be regulated by NSAIDs to inhibit growth. The p75 neurotrophin receptor (p75^NTR) is a proximate cell membrane receptor glycoprotein that has been identified as a tumor and metastasis suppressor. We observed that NSAID treatment of cell lines from bladder and other organs induced expression of the p75^NTR protein. Of the different types of NSAIDs examined, ibuprofen was more efficacious than aspirin and acetaminophen and comparable with (R)-flurbiprofen and indomethacin in induction of p75^NTR protein expression. This rank order NSAID induction of the p75^NTR protein correlated with the ability of these NSAIDs to reduce cancer cell survival. To examine a mechanistic relationship between ibuprofen induction of p75^NTR protein and inhibition of survival, bladder cancer cells were transfected with ponasterone A-inducible vectors that expressed a death domain-deleted (DD) or intracellular domain-deleted (ICD) p75^NTR product that acts as a dominant negative antagonist of the intact p75^NTR protein. Expression of DD and ICD rescued cells from ibuprofen inhibition of growth. These observations suggest that p75^NTR is an important upstream modulator of the anticancer effects of NSAIDs and that ibuprofen induction of the p75^NTR protein establishes an alternate mechanism by which ibuprofen may exert an anticancer effect.

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