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Di Marcantonio D , Martinez E , Sidoli S , Vadaketh J , Nieborowska-Skorska M , Gupta A , Meadows JM , Ferraro F , Masselli E , Challen GA , Milsom MD , Scholl C , Froehling S , Balachandran S , Skorski T , Garcia B , Mirandola P , Gobbi G , Garzon R , Vitale M , Sykes SM
PKC epsilon is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia
Clin Cancer Res. 2018 Feb 1;24(3) :608-618
PMID: 29127121    PMCID: PMC5796864    URL: https://www.ncbi.nlm.nih.gov/pubmed/29127121
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PURPOSE: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown. EXPERIMENTAL DESIGN AND RESULTS: We show that RNA interference-mediated inhibition of the serine/threonine kinase PKC-epsilon (PKCe) reduces cell survival in a diverse panel of patient-derived AML samples and significantly delays disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. Utilizing a combination of chemical and genetically-encoded redox sensing probes, we found that PKCe inhibition leads to the induction of multiple reactive oxygen species (ROS) including multiple mitochondrial ROS. We also show that neutralization of mitochondrial ROS with chemical anti-oxidants or co-expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigate the anti-leukemia effects of PKCe inhibition. Similar to PKCe inhibition, direct inhibition of SOD2 also increases mitochondrial ROS and significantly impedes disease progression in vivo. Furthermore, we report that over-expression of PKCe protects AML cells from otherwise-lethal doses of mitochondrial ROS-inducing agents. Proteomic analysis reveals that PKCe may control mitochondrial ROS by controlling the expression of regulatory proteins of redox homeostasis, electron transport chain flux, as well as outer mitochondrial membrane potential and transport. CONCLUSIONS: This study uncovers a previously unrecognized role for PKCepsilon in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML.
Di Marcantonio, Daniela Martinez, Esteban Sidoli, Simone Vadaketh, Jessica Nieborowska-Skorska, Margaret Gupta, Anushk Meadows, Jacob Michael Ferraro, Francesca Masselli, Elena Challen, Grant A Milsom, Michael D Scholl, Claudia Froehling, Stefan Balachandran, Siddharth Skorski, Tomasz Garcia, Benjamin Mirandola, Prisco Gobbi, Giuliana Garzon, Ramiro Vitale, Marco Sykes, Stephen M R01 DK102428/DK/NIDDK NIH HHS/United States Journal Article United States Clin Cancer Res. 2017 Nov 10. pii: 1078-0432.CCR-17-2684. doi: 10.1158/1078-0432.CCR-17-2684.