Faculty Collaboration Database

AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake. PLoS One 2014;9(4):e92948

Date

04/08/2014

Pubmed ID

24705275

Pubmed Central ID

PMC3976291

DOI

10.1371/journal.pone.0092948

Scopus ID

2-s2.0-84899414047 (requires institutional sign-in at Scopus site)   77 Citations

Abstract

BACKGROUND: 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.

EXPERIMENTAL DESIGN: Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233*) 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 18F-fluorodeoxyglucose (FDG). Cell migration was assessed by scratch assay.

RESULTS: Activating PIK3CA (E545K, E542K) and inactivating PTEN (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.

CONCLUSIONS: 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 in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.

Author List

Rashmi R, DeSelm C, Helms C, Bowcock A, Rogers BE, Rader JL, Rader J, Grigsby PW, Schwarz JK

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Cell Death
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Cyclohexanones
Female
Glucose
Heterocyclic Compounds, 3-Ring
Humans
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Pyridines
Signal Transduction
TOR Serine-Threonine Kinases
Uterine Cervical Neoplasms