Morphoproteomics identifies constitutive activation of the mTORC2/Akt and NF-κB pathways and expressions of IGF-1R, Sirt1, COX-2, and FASN in peripheral T-cell lymphomas: pathogenetic implications and therapeutic options

Background: Gaining a better understanding of the molecular circuitries and pathways implicated in the malignant growth and biological behavior of T cell lymphomas may identify potential cellular targets with clinical therapeutic potential. The immunohistochemical characterization of key cellular proteins participating in these pathways can provide surrogate markers of biological activity. The mammalian target of rapamycin complex (mTORC) signaling pathway has been implicated in T-cell lymphopoiesis. The mTORC2 pathway involves downstream activation of nuclear factor (NF)-kappa B and p-Akt (Ser 473). Fatty acid synthase (FASN) and insulin-like growth factor-1 receptor (IGF-1R) are expressed upstream of the mTORC and NF-kappa B signaling pathways. Cyclooxygenase (COX)-2 products influence these pathways. Our goal was to use morphoproteomics to characterize the expression patterns of the proteins in various peripheral T-cell lymphomas. Design: Ten cases of peripheral T-cell lymphoma (PTCL) were examined for expression of proteins along the mTORC, Akt and NF-kappa B pathways and affiliated tumorigenic molecules. These included two angioimmunoblastic PTCL, one natural killer/PTCL, one anaplastic large PTCL, and six PTCL not otherwise specified. Immunostaining for phosphorylated (p) mTOR (Ser 2448), p-Akt (Ser 473), p-NF-kappa Bp65 (Ser 536), IGF-1R (Tyr1165/1166), silent mating type information regulation 2 homolog 1 (Sirt1), COX-2 and FASN was performed on paraffin-embedded tissue for each case. Percent expression was scored using bright-field microscopy with high expression designated as more than 50% of the cells with positive stain in the appropriate subcellular compartment. Results: All ten cases demonstrated nuclear staining for p-mTOR (Ser 2448) corresponding to mTORC 2, and all cases showed strong, diffuse nuclear staining for p-NF-kappa Bp65 (Ser 536). All ten also showed nuclear and cytoplasmic staining for p-Akt (Ser 473) and cytoplasmic staining for IGF-1R. High expressions for nuclear Sirt1, and cytoplasmic COX-2 and FASN were detected in 7, 9, and 8 out of 10 cases, respectively. Six out of 10 cases demonstrated high expression of all the mentioned markers. Conclusion: The constitutive activation of mTORC2, NF-kappa B, p-Akt and the concomitant expression of IGF-1R suggests convergence of these molecular pathways in T-cell lymphoma. The results of this study also suggest that mTORC2 may be a common denominator among this heterogeneous group of lymphomas. Interference of key nodes of this pathway may carry a clinical therapeutic benefit. Agents that may be considered based on existing data include: bortezomib to inhibit NF-kappa B pathway activation; metformin to inhibit both NF-kappa B and mTORC2 and histone deacteylase inhibitors to inhibit mTORC2 pathway signaling. Furthermore, panobinostat inhibits Sirt1 pathway when present, and celecoxib inhibits NF-kappa B pathway activation independent of COX2.