AKT Inhibitors Promote Cell Death in Cervical Cancer through Disruption of mTOR Signaling and Glucose Uptake RashmiRamachandran DeSelmCarl HelmsCynthia BowcockAnne RogersBuck E. RaderJanet W. GrigsbyPerry K. SchwarzJulie 2014 <div><p>Background</p><p>PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability.</p><p>Experimental Design</p><p>Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (<i>PIK3CAR88Q</i> and <i>PTENR233*</i>) were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206) with or without the glucose analogue 2-deoxyglucose (2-DG). Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with <sup>18</sup>F-fluorodeoxyglucose (FDG). Cell migration was assessed by scratch assay.</p><p>Results</p><p>Activating <i>PIK3CA</i> (E545K, E542K) and inactivating <i>PTEN</i> (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) and MK-2206 (30 µM-49%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment.</p><p>Conclusions</p><p>The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability <i>in vitro</i>. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.</p></div>