mTOR pathway activation in multiple myeloma cell lines and primary tumour cells: pomalidomide enhances cytoplasmic-nuclear shuttling of mTOR protein
Tommasina Guglielmelli1, Emilia Giugliano1, Vanessa Brunetto1, Ida Rapa2, Susanna Cappia2, Jessica Giorcelli2, Sokol Rrodhe1, Mauro Papotti2, Giuseppe Saglio1
1 Department of Clinical and Biological Sciences, University of Turin and S Luigi Hospital, Orbassano, Turin, Italy
2 Department of Oncology, University of Turin and S Luigi Hospital, Orbassano, Turin, Italy
Correspondence:
Tommasina Guglielmelli, email:
Keywords: multiple myeloma, pomalidomide, mTOR pathway, nuclear, AKT
Received: January 13, 2015 Accepted: March 16, 2015 Published: April 6, 2015
Abstract
mTOR is a protein kinase that plays a central role in regulating critical cellular processes. We evaluated the activation and cellular localization of the mTOR pathway in multiple myeloma (MM) and analyzed the role of pomalidomide in regulating mTOR. By immunohistochemistry cytoplasmic p-mTOR stained positive in 57 out 101 (57.6%) cases with a nuclear p-mTOR localization in 14 out 101 samples (13.8%). In the 70 MM samples analyzed for the entire pathway, p-mTOR expression significantly correlated with p-AKT, p-P70S6K, and p-4E-BP1 suggesting that the AKT/mTOR pathway is activated in a subset of MM patients. Immunofluorescence assays demonstrated that mTOR protein is distributed throughout the cytoplasm and the nucleus at baseline in MM cell lines and in plasma cells of 13 MM patients and that pomalidomide facilitated the shift of the mTOR protein in the nucleus. By western blotting, treatment with pomalidomide increased nuclear mTOR and p-mTOR expression levels in the nucleus with a concomitant decrease of the cytoplasmic fractions while does not seem to affect significantly AKT phosphorylation status. In MM cells the anti-myeloma activity of pomalidomide may be mediated by the regulation of the mTOR pathway.
