Prostate tumor specimens express high level of Prostate Specific Membrane Antigen (PMSA) associated in 50%-60% of cases with activation of anti apoptotic signaling pathways, transactivators and cytokines genes. Integrins are aberrantly expressed as their signaling adaptor p130CAS. We have previously demonstrated that clustering PSMA with specific mAbs signals to RAS-RAC-MAPK pathway activation, NF-kB translocation, IL-6 gene expression and proliferation in LNCaP cells. Our recent data show that PSMA activates both AKT/mTOR/BAD and MAPK pathways thereby rescuing LNCaP cells from apoptosis. PSMA activity relies on a Filamin A-mediated cooperation with beta1 integrin. PSMA clustering triggers the exposure of HUTS-21 activation epitope on beta1 integrin and the assembling of a complex including PSMA, Filamin A, beta1 integrin, p130CAS and Src1. All these molecules co-localize in the same lipid rafts. PSMA-mediated exposure of HUTS-21 epitope was almost abrogated by Filamin A silencing or Src1 inhibition by PP1. ERK1/2 and AKT phosphorylations were hampered by Filamin A or beta1 silencing or Src1 inhibition. These results first highlights that PSMA/beta1 integrin cooperation regulates apoptosis resistence of LNCaP cells. Moreover they show that the bridging activity of Filamin A can extend the partnership of beta1 integrin to molecules other than growth factors or cytokine receptors.

Cooperation of Prostate Specific Membrane Antigen with beta 1 integrin promotes the survival of aggressive prostate cancer cells

GRASSO, Silvia;Perico, Maria Elisa;SHUKLA, Priyanka;FRACASSO, Giulio;COLOMBATTI, Marco;RAMARLI, DUNIA
2012

Abstract

Prostate tumor specimens express high level of Prostate Specific Membrane Antigen (PMSA) associated in 50%-60% of cases with activation of anti apoptotic signaling pathways, transactivators and cytokines genes. Integrins are aberrantly expressed as their signaling adaptor p130CAS. We have previously demonstrated that clustering PSMA with specific mAbs signals to RAS-RAC-MAPK pathway activation, NF-kB translocation, IL-6 gene expression and proliferation in LNCaP cells. Our recent data show that PSMA activates both AKT/mTOR/BAD and MAPK pathways thereby rescuing LNCaP cells from apoptosis. PSMA activity relies on a Filamin A-mediated cooperation with beta1 integrin. PSMA clustering triggers the exposure of HUTS-21 activation epitope on beta1 integrin and the assembling of a complex including PSMA, Filamin A, beta1 integrin, p130CAS and Src1. All these molecules co-localize in the same lipid rafts. PSMA-mediated exposure of HUTS-21 epitope was almost abrogated by Filamin A silencing or Src1 inhibition by PP1. ERK1/2 and AKT phosphorylations were hampered by Filamin A or beta1 silencing or Src1 inhibition. These results first highlights that PSMA/beta1 integrin cooperation regulates apoptosis resistence of LNCaP cells. Moreover they show that the bridging activity of Filamin A can extend the partnership of beta1 integrin to molecules other than growth factors or cytokine receptors.
PSMA; integrin; survival; cancer; prostate
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/510793
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