title: Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia.
abstract: Alterations of cellular metabolism represent a hallmark of cancer. Numerous metabolic changes are required for malignant transformation, and they render malignant cells more prone to disturbances in the metabolic framework. Despite the high incidence of chronic lymphocytic leukemia (CLL), metabolism of CLL cells remains a relatively unexplored area. The examined untreated CLL patients displayed a metabolic condition known as oxidative stress, which was linked to alterations in their lymphoid compartment. Our studies identified mitochondrial metabolism as the key source for abundant reactive oxygen species (ROS). Unlike in other malignant cells, we found increased oxidative phosphorylation in CLL cells but not increased aerobic glycolysis. Furthermore, CLL cells adapted to intrinsic oxidative stress by upregulating the stress-responsive heme-oxygenase-1 (HO-1). Our data implicate that HO-1 was, beyond its function as an antioxidant, involved in promoting mitochondrial biogenesis. Thus ROS, adaptation to ROS, and mitochondrial biogenesis appear to form a self-amplifying feedback loop in CLL cells. Taking advantage of the altered metabolic profile, we were able to selectively target CLL cells by PK11195. This benzodiazepine derivate blocks the mitochondrial F1F0-ATPase, leads to a surplus production of mitochondrial superoxide, and thereby induces cell death in CLL cells. Taken together, our findings depict how bioenergetics and redox characteristics could be therapeutically exploited in CLL.
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, and.
authors.forename: Regina
authors.initials: R
authors.lastname: Jitschin
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Hofmann
authors.forename: Heiko
authors.initials: H
authors.lastname: Bruns
authors.forename: Andreas
authors.initials: A
authors.lastname: Giessl
authors.forename: Juliane
authors.initials: J
authors.lastname: Bricks
authors.forename: Jana
authors.initials: J
authors.lastname: Berger
authors.forename: Domenica
authors.initials: D
authors.lastname: Saul
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eckart
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mougiakakos
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D016207:Cytokines / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016207:Cytokines; D007546:Isoquinolines; D017382:Reactive Oxygen Species; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000251:Adenosine Triphosphatases; D005978:Glutathione; C037850:PK 11195