![]() Because excessive oxidative stress can lead to senescence or cell death, proliferating cancer cells limit cellular ROS levels by inducing an array of antioxidants and ROS scavengers ( 9). Treatment with PIM kinase inhibitors reverses this resistance phenotype, making tumors increasingly susceptible to small-molecule therapeutics, which block the PI3K-AKT pathway.Īctivation of the AKT pathway produces reactive oxygen species (ROS). ![]() Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. PIM prevents cell death induced by PI3K-AKT–inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. ![]() However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. ![]()
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