Abstract
Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance.
Highlights
Published: 21 October 2021Serine-threonine kinase AKT is a key component of multiple signaling pathways in mammalian cells [1]
While the enzymes from the PI3K family contribute to the activation of AKT via the production of phospholipids, the reverse reaction catalyzed by the Phosphatase and TEnsin Homolog (PTEN) phosphatase serves to curtail AKT activity [3]
We explore the relationship between hyperactivation of AKT and the heat shock response in non-tumor-derived cells, which are less likely to carry secondary adaptive alterations acquired in the course of a prolonged tumor evolution
Summary
Serine-threonine kinase AKT is a key component of multiple signaling pathways in mammalian cells [1]. Therapeutic strategies to increase its lethality by either facilitating additional protein damage or inhibiting detoxifying mechanisms have garnered some evidence of success in clinical and pre-clinical studies of cancer therapy and prevention [25] In this current report, we explore the relationship between hyperactivation of AKT and the heat shock response in non-tumor-derived cells, which are less likely to carry secondary adaptive alterations acquired in the course of a prolonged tumor evolution. Sci. 2021, 22, 11376 ing mechanisms have garnered some evidence of success in clinical and pre-clinical studies of cancer therapy and prevention [25] In this current report, we explore the relationship between hyperactivation of AKT and the heat shock response in non-tumor-derived cells, which are less likely to carry secondary adaptive alterations acquired in the course. Results often marks the progression from a pre-malignant to a malignant lesion, or the evolution
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