ABSTRACT
A deregulated activity of PKB/Akt (where PKB stands for protein kinase B) renders tumour cells resistant to a variety of apoptosis-inducing stimuli. Elucidation of the mechanisms responsible for this deregulation is of prime importance for the development of novel anti-cancer drugs. Results of the present study demonstrate that the constitutive activity of PKB/Akt in B16BL6 melanoma cells depends on the integrity of cholesterol-enriched membrane microdomains, since the exposure of cells to cholesterol-depleting agents decreases the phosphorylation of this enzyme, with no change in its total protein level. Inhibitors of Hsp90 (heat-shock protein 90) decreased phosphorylation of PKB/Akt with a similar pattern. Dephosphorylation of the enzyme, as a consequence of raft disintegration, could be precluded by inhibition of serine/threonine (but not tyrosine) phosphatases. Our results imply that destabilization of lipid rafts seemingly affects the association of Hsp90 with the respective serine/threonine phosphatases, thereby increasing the accessibility to PKB/Akt to deactivating phosphatases. We have found recently that reconstituted expression of H-2K class I glycoproteins in class I-deficient B16BL6 cells also decreases the phosphorylation of PKB/Akt. Therefore it is possible that raft-associated regulation of this important enzyme involves both H-2K glycoproteins and Hsp90.
Subject(s)
Cholesterol/metabolism , Membrane Microdomains/chemistry , Neoplasms/metabolism , Protein Serine-Threonine Kinases/biosynthesis , Protein Serine-Threonine Kinases/physiology , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/physiology , Animals , Antineoplastic Agents/pharmacology , Glycoproteins/chemistry , HSP90 Heat-Shock Proteins/chemistry , Melanoma, Experimental , Mice , Novobiocin/chemistry , Phosphorylation , Proto-Oncogene Proteins c-aktABSTRACT
MHC class I glycoproteins play a pivotal role in the regulation of immune responses by presenting antigenic peptides to cytotoxic T lymphocytes and by regulating cytolytic activities of natural killer cells. Cells originating in malignant tumours are often characterized by a profound immune escape phenotype. This phenotype is frequently associated with alterations in MHC class I-related antigen processing and presentation that enable tumours to escape immune surveillance. However, it now becomes clear that MHC class I molecules do not only provide a mechanistic framework for the presentation of antigenic peptides but, rather, possess broader biological functions due to their ability to regulate cell-to-cell communication and receptor-mediated trans-membrane signal transduction. In the present review we made an attempt to reevaluate the significance of an altered MHC class I phenotype for tumour progression in view of the current state of knowledge concerning the aforementioned non-immune functions performed by these membrane glycoproteins.
