Tumor suppressor WWOX moderates the mitochondrial respiratory complex

Abstract

Fragile site FRA16D exhibits DNA instability in cancer, resulting in diminished levels of protein from the WWOX gene that spans it. WWOX suppresses tumor growth by an undefined mechanism. WWOX participates in pathways involving aerobic metabolism and reactive oxygen species. WWOX comprises two WW domains as well as a short-chain dehydrogenase/reductase enzyme. Herein is described an in vivo genetic analysis in Drosophila melanogaster to identify functional interactions between WWOX and metabolic pathways. Altered WWOX levels modulate variable cellular outgrowths caused by genetic deficiencies of components of the mitochondrial respiratory complexes. This modulation requires the enzyme active site of WWOX, and the defective respiratory complex-induced cellular outgrowths are mediated by reactive oxygen species, dependent upon the Akt pathway and sensitive to levels of autophagy and hypoxia-inducible factor. WWOX is known to contribute to homeostasis by regulating the balance between oxidative phosphorylation and glycolysis. Reduction of WWOX levels results in diminished ability to respond to metabolic perturbation of normal cell growth. Thus, the ability of WWOX to facilitate escape from mitochondrial damage-induced glycolysis (Warburg effect) is, therefore, a plausible mechanism for its tumor suppressor activity.

Tumor Suppressor WWOX Contributes to the Elimination of Tumorigenic Cells in Drosophila melanogaster

“…At least to some extent, this occurs through regulation of the subset of ROS that are also responsive to enzymes of the superoxide dismutase (SOD) family and we have previously shown alterations in isoforms of SOD1 in WWOX mutant flies as well as genetic interactions between WWOX and SOD1 [ 30 ]. However the role for WWOX in the regulation of ROS levels may occur in a context dependent manner given the opposing effects reported for altered ROS in response to modified WWOX expression [ 61 – 62 ]. In addition, alterations to ROS levels would occur as a consequence of cancer cells shifting their metabolism from oxidative phosphorylation to a more glycolytic Warburg-based metabolism and we have previously shown that WWOX is both responsive to, and contributes to aerobic metabolism [ 30 – 31 ].…”

“…Ectopic Eiger/TNFα expression stock ( UAS-egr +w ) was kindly provided by Professor Miura [ 46 ]. WWOX 1 , WWOX 2 , UAS-WWOX ORF #1 and UAS-WWOX cDNA #1 have previously been described [ 49 and 61 ]. MARCMIII and FRT82B , Scrib 1 stocks were kindly provided by Helena Richardson.…”

Role of WW Domain-containing Oxidoreductase WWOX in Driving T Cell Acute Lymphoblastic Leukemia Maturation

“…We have previously reported the presence of WWOX and p53 in the mitochondria (22,39,44). In addition, WWOX is involved in mitochondrial respiration and metabolism (45,46). By co-immunoprecipitation, yeast two-hybrid analysis, timelapse FRET microscopy, and expression of cloned plasmid vectors, we deciphered how the component proteins in the complex interact with each other and how the action contributes to MOLT-4 maturation.…”

Zfra restores memory deficits in Alzheimer's disease triple‐transgenic mice by blocking aggregation of TRAPPC6AΔ, SH3GLB2, tau, and amyloid β, and inflammatory NF‐κB activation

“…However, transiently overexpressed WWOX induces mitochondrial apoptosis in vitro [21] , [22] . Transgenic mutant WWOX proteins cause mitochondrial dysfunction by affecting the respiratory complex in Drosophila [23] .…”