TY - JOUR
T1 - Protein kinase C epsilon is a key regulator of mitochondrial redox homeostasis in acute myeloid leukemia
AU - Di Marcantonio, Daniela
AU - Martinez, Esteban
AU - Sidoli, Simone
AU - Vadaketh, Jessica
AU - Nieborowska-Skorska, Margaret
AU - Gupta, Anushk
AU - Meadows, Jake M.
AU - Ferraro, Francesca
AU - Masselli, Elena
AU - Challen, Grant A.
AU - Milsom, Michael D.
AU - Scholl, Claudia
AU - Frohling, Stefan
AU - Balachandran, Siddharth
AU - Skorski, Tomasz
AU - Garcia, Benjamin A.
AU - Mirandola, Prisco
AU - Gobbi, Giuliana
AU - Garzon, Ramiro
AU - Vitale, Marco
AU - Sykes, Stephen M.
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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: Utilizing several chemical and genetically-encoded redox sensing probes across multiple human and mouse models of AML, we evaluated the role of the serine/ threonine kinase PKC-epsilon (PKCe) in intracellular redox biology, cell survival and disease progression. Results: We show that RNA interference-mediated inhibition of PKCe significantly reduces patient-derived AML cell survival as well as disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. We also show that PKCe inhibition induces multiple reactive oxygen species (ROS) and that neutralization of mitochondrial ROS with chemical antioxidants or co-expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigates the anti-leukemia effects of PKCe inhibition. Moreover, direct inhibition of SOD2 increases mitochondrial ROS and significantly impedes AML progression in vivo. Furthermore, we report that PKCe over-expression 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 PKCe in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML.
AB - 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: Utilizing several chemical and genetically-encoded redox sensing probes across multiple human and mouse models of AML, we evaluated the role of the serine/ threonine kinase PKC-epsilon (PKCe) in intracellular redox biology, cell survival and disease progression. Results: We show that RNA interference-mediated inhibition of PKCe significantly reduces patient-derived AML cell survival as well as disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. We also show that PKCe inhibition induces multiple reactive oxygen species (ROS) and that neutralization of mitochondrial ROS with chemical antioxidants or co-expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigates the anti-leukemia effects of PKCe inhibition. Moreover, direct inhibition of SOD2 increases mitochondrial ROS and significantly impedes AML progression in vivo. Furthermore, we report that PKCe over-expression 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 PKCe in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML.
KW - Animals
KW - Apoptosis/drug effects
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Cell Survival
KW - Gene Expression Regulation, Leukemic
KW - Homeostasis
KW - Humans
KW - Intracellular Space/metabolism
KW - Leukemia, Myeloid, Acute/genetics
KW - Mice
KW - Mitochondria/metabolism
KW - Oxidation-Reduction
KW - Protein Kinase C-epsilon/metabolism
KW - Reactive Oxygen Species/metabolism
KW - Superoxide Dismutase/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85041454462&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-2684
DO - 10.1158/1078-0432.CCR-17-2684
M3 - Article
C2 - 29127121
SN - 1078-0432
VL - 24
SP - 608
EP - 618
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -