Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma.
Kaposi's sarcoma (KS) is an enigmatic vascular neoplasm that has reached epidemic proportions in parts of the developing world and is a leading cause of morbidity and mortality among the AIDS population. Unfortunately, KS is still difficult to manage therapeutically, especially in its most advanced clinical manifestations. The recent identification of the KS-associated herpesvirus (KSHV or HHV8) as its viral etiologic agent has prompted renewed interest in the molecular pathogenesis of this disease. Emerging evidence now points to a single KSHV gene, vGPCR, as essential for KS development, providing a unique opportunity to expose new targets for the treatment of this tumor. In this regard, recent work has identified the Akt/TSC/mTOR signaling cascade as a critical pathway in vGPCR sarcomagenesis. Indeed, pharmacological inhibition of mTOR with rapamycin has shown promising results in preventing vGPCR tumorigenesis in an animal model for KS. These observations are further validated by coincident reports demonstrating the efficacy of rapamycin (sirolimus) as an immunossuppresive and anti-tumoral solution for posttransplant KS patients. Collectively, these data suggest that inhibition of the Akt/TSC/mTOR signaling pathway may provide a novel molecular-based approach for the treatment of patients who currently have a paucity of therapeutic options.
Montaner
Silvia
S
Greenebaum Cancer Center; and Department of Diagnostic Sciences and Pathology; University of Maryland, Baltimore; 650 West Baltimore Street; 7th North, Rm 7263; Baltimore, Maryland 21201 USA. s montaner@umaryland.edu
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D002135:Calcium-Binding Proteins; C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine; C486009:TESC protein, human; D014764:Viral Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus