Constitutive Activation of the mTORC2 and NF-kappaB Pathways and High Expression of SIRT1, COX-2 and FASN in T-Cell Lymphomas with Therapeutic Implications
Andres E Quesada, Robert E Brown, Adan Rios, Nghia D Nguyen. University of Texas at Houston, Houston, TX
Background: Increasing knowledge of the molecular biology of T cell lymphomas (TCL) has begun to identify pathways implicated in their malignant growth and biological behavior. The immunohistochemical characterization of key participating cellular proteins provides markers of biological activity and identifies potential therapeutic targets. Tang, et al. implicated the mammalian target of rapamycin complex (mTORC) signaling pathway in T-cell lymphopoiesis. The mTORC2 pathway involves downstream activation of NF-κB. Fatty acid synthase (FASN) and COX-2 are expressed upstream and downstream, respectively of NF-κB. To our knowledge, there have been no studies utilizing morphoproteomics to analyze the expression of specific proteins in the mTORC2 signaling pathway in TCL.
Design: Ten cases of TCL cases were examined for expression of proteins along the mTORC signaling pathway. These included two angioimmunoblastic TCL, one natural killer/TCL, one anaplastic large TCL, and six TCL NOS. Immunostaining for COX-2, FASN, phosphorylated (p) mTOR [Ser 2448], p-NF-κBp65(Ser 536), SIRT1, and Bcl-2 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-κBp65 (Ser 536). High expressions for nuclear SIRT1, and cytoplasmic FASN were detected in 7 and 8 out of 10 cases, respectively. All but one case showed strong and diffuse expression of COX-2, a downstream effector of NF-κB. Of note, 5 out of 10 cases demonstrate high expression of all the mentioned markers.
Conclusions: Constitutive activation of mTORC2 and NF-κB pathways indicate convergence on the NF-κB molecular pathway in TCL. The mTORC2 appears to be a common denominator among this heterogeneous group. 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-κB, metformin to inhibit NF-κB and mTORC2 and histone deacteylase inhibitors to inhibit mTORC2 pathway signaling. Furthermore, panobinostat inhibits SIRT1 pathway when present, and celecoxib inhibits NF-kappaB pathway signaling independent of COX2.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 229, Monday Morning