Prostate cancer (Pc) is the second cause of cancer-related death in males of Western countries, due to the poor prognosis of the advanced, androgen-independent, metastatic disease. Advanced Pc cells over-express PSMA, in a drug-resistant, apoptosis-insensitive cell microenvironment where PI3K/AKT/mTOR and RAF/MEK/ERK pathways are constitutively activated, STAT3/NF-kB transactivators increase their function, IL-6 expression is maximized and betat1/beta3 integrins are aberrantly or overexpressed. Whether and how PSMA acts in the generation/maintenance of the advanced Pc phenotype was the topic of our study. PSMA is a trans-membrane folate-hydrolase/carboxypeptidase bearing a binding site for Filamin A (FLNa) in its cytodomain. Previous and herein detailed results by our group demonstrate that PSMA cross-linking signals to PI3K/AKT/mTOR and RAF/MEK/ERK1/2 activation in LNCaP cells (a cell model of advance Pc) and rescues LNCaP from apoptotic stimuli. Both pathways regulate survival and PSMA-mediated rescue. The relevance of FLNa-mediated PSMA/beta1 interaction in these phenomena was shown by the finding that:i) PSMA and beta1 co-localized at the surface of LNCaP cells ii) PSMA cross-linking induced the exposure of HUTS-21 activation epitopes on beta1 and the assembly of a complex including PSMA itself, FLNa, beta1 integrin, pp130CAS and pSrc iii) PSMA- mediated beta1 activation, AKT or ERK1/2 phosphorylation were all hampered by FLNa silencing or Src inhibition with PP1.Collectively, these results first highlights a key role for PSMA/beta1 integrin cooperation in regulating the activation state of advanced Pc cells. Moreover they show that the bridging activity of FLNa can extend the cross-talk of beta1 cytodomain to molecules other than growth factors or cytokine receptors.
Filamin A-mediated interaction of Prostate Specific Membrane Antigen (PSMA) with beta1 integrin regulates survival of advanced prostate cancer cells
GRASSO, Silvia;SHUKLA, Priyanka;Perico, Maria Elisa;FRACASSO, Giulio;RAMARLI, DUNIA
2011-01-01
Abstract
Prostate cancer (Pc) is the second cause of cancer-related death in males of Western countries, due to the poor prognosis of the advanced, androgen-independent, metastatic disease. Advanced Pc cells over-express PSMA, in a drug-resistant, apoptosis-insensitive cell microenvironment where PI3K/AKT/mTOR and RAF/MEK/ERK pathways are constitutively activated, STAT3/NF-kB transactivators increase their function, IL-6 expression is maximized and betat1/beta3 integrins are aberrantly or overexpressed. Whether and how PSMA acts in the generation/maintenance of the advanced Pc phenotype was the topic of our study. PSMA is a trans-membrane folate-hydrolase/carboxypeptidase bearing a binding site for Filamin A (FLNa) in its cytodomain. Previous and herein detailed results by our group demonstrate that PSMA cross-linking signals to PI3K/AKT/mTOR and RAF/MEK/ERK1/2 activation in LNCaP cells (a cell model of advance Pc) and rescues LNCaP from apoptotic stimuli. Both pathways regulate survival and PSMA-mediated rescue. The relevance of FLNa-mediated PSMA/beta1 interaction in these phenomena was shown by the finding that:i) PSMA and beta1 co-localized at the surface of LNCaP cells ii) PSMA cross-linking induced the exposure of HUTS-21 activation epitopes on beta1 and the assembly of a complex including PSMA itself, FLNa, beta1 integrin, pp130CAS and pSrc iii) PSMA- mediated beta1 activation, AKT or ERK1/2 phosphorylation were all hampered by FLNa silencing or Src inhibition with PP1.Collectively, these results first highlights a key role for PSMA/beta1 integrin cooperation in regulating the activation state of advanced Pc cells. Moreover they show that the bridging activity of FLNa can extend the cross-talk of beta1 cytodomain to molecules other than growth factors or cytokine receptors.
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