Abstract
Akt activation in human cancers exerts chemoresistance, but pan-Akt inhibition elicits adverse consequences. We exploited the consequences of Akt-mediated mitochondrial and glucose metabolism to selectively eradicate and evade chemoresistance of prostate cancer displaying hyperactive Akt. PTEN-deficient prostate cancer cells that display hyperactivated Akt have high intracellular reactive oxygen species (ROS) levels, in part, because of Akt-dependent increase of oxidative phosphorylation. High intracellular ROS levels selectively sensitize cells displaying hyperactive Akt to ROS-induced cell death enabling a therapeutic strategy combining a ROS inducer and rapamycin in PTEN-deficient prostate tumors in mouse models. This strategy elicited tumor regression, and markedly increased survival even after the treatment was stopped. By contrast, exposure to antioxidant increased prostate tumor progression. To increase glucose metabolism, Akt activation phosphorylated HK2 and induced its expression. Indeed, HK2 deficiency in mouse models of Pten-deficient prostate cancer elicited a marked inhibition of tumor development and extended lifespan.
Highlights
One of the most frequent events in human cancer is hyperactivation of the serine/threonine kinase Akt
Basal oxygen consumption was lowest in the Phosphatase And Tensin Homolog (PTEN)-proficient DU145 cells, while it was gradually increased in the PTEN-deficient PC3 and LNCaP cells (Figure 1B), following the pattern of Akt activity in which higher oxygen consumption was correlated with higher Akt activity
When tumor sections were analyzed after 8 months, we found that all treatments markedly inhibited proliferation, as measured by BrdU incorporation (Figure 3D and E), but phenylethyl isothiocyanate (PEITC) induced cell death, which was further exacerbated when PEITC was combined with rapamycin (Figure 3D and F)
Summary
One of the most frequent events in human cancer is hyperactivation of the serine/threonine kinase Akt. The activity of PI3K is negatively regulated by the tumor suppressor Phosphatase And Tensin Homolog (PTEN), which is a PIP3 phosphatase, and inhibits the PI3K/Akt signaling pathway. The activation of PI3K/Akt signaling in cancer and its ability to exert chemoresistance led to the development of small molecule inhibitors of PI3K and Akt, which are currently being tested in clinical trials (Kim et al, 2005; Zhang et al, 2017; Zheng, 2017). There are three Akt genes in mammalian cells (Akt1-3), and their encoded proteins have a high degree of identical amino acids; the expression pattern in mammalian tissues and organs is different among the three isoforms.
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