PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1alpha.
Tumor cell resistance to ionizing radiation and chemotherapy is a major obstacle in cancer therapy. One factor contributing to this is integrin-mediated adhesion to ECM. The adapter protein particularly interesting new cysteine-histidine-rich 1 (PINCH1) is recruited to integrin adhesion sites and promotes cell survival, but the mechanisms underlying this effect are not well understood. Here we have shown that PINCH1 is expressed at elevated levels in human tumors of diverse origins relative to normal tissue. Furthermore, PINCH1 promoted cell survival upon treatment with ionizing radiation in vitro and in vivo by perpetuating Akt1 phosphorylation and activity. Mechanistically, PINCH1 was found to directly bind to protein phosphatase 1alpha (PP1alpha) - an Akt1-regulating protein - and inhibit PP1alpha activity, resulting in increased Akt1 phosphorylation and enhanced radioresistance. Thus, our data suggest that targeting signaling molecules such as PINCH1 that function downstream of focal adhesions (the complexes that mediate tumor cell adhesion to ECM) may overcome radio- and chemoresistance, providing new therapeutic approaches for cancer.
Eke
Iris
I
OncoRay - Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany.
Koch
Ulrike
U
Hehlgans
Stephanie
S
Sandfort
Veit
V
Stanchi
Fabio
F
Zips
Daniel
D
Baumann
Michael
M
Shevchenko
Anna
A
Pilarsky
Christian
C
Haase
Michael
M
Baretton
Gustavo B
GB
Calleja
Véronique
V
Larijani
Banafshé
B
Fässler
Reinhard
R
Cordes
Nils
N
D048868:Adaptor Proteins, Signal Transducing; D002448:Cell Adhesion / Q000502:physiology; D002470:Cell Survival; D003545:Cysteine / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology; D022001:Focal Adhesions / Q000378:metabolism / Q000502:physiology; D006639:Histidine / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D016023:Integrins; D060588:LIM Domain Proteins; C088088:LIMS1 protein, human; D008565:Membrane Proteins; D006639:Histidine; D051057:Proto-Oncogene Proteins c-akt; D054645:Protein Phosphatase 1; D003545:Cysteine