Issues

Chin and colleagues found that knockdown or pharmacologic inhibition of AKT2 but not AKT1 induced apoptosis in established tumor spheroids derived from PTEN-deficient prostate, breast, and glioblastoma cell lines, indicating that this isoform is essential for PTEN-deficient tumor survival. AKT2 depletion resulted in upregulation of p21 and BAX and downregulation of insulin-like growth factor 1 receptor; knockdown of p21, but not BAX, rescued apoptosis induced by AKT2 depletion, suggesting that p21 is a downstream target of AKT2. Importantly, although AKT1 silencing exhibited a largely cytostatic effect in prostate cancer xenografts, AKT2 depletion increased p21 levels, stimulated apoptosis, and promoted tumor regression. These results indicate that AKT2 is required for the maintenance of PTEN-deficient tumors and highlight the need for preclinical development of AKT2-selective inhibitors. For details, please see the article by Chin and colleagues on page 942.