WWOX Modulates ROS-Dependent Senescence in Bladder Cancer

Abstract

The tumor-suppressor gene, WW domain-containing oxidoreductase (WWOX), has been found to be lost in various types of cancers. ROS result as a tightly regulated signaling process for the induction of cell senescence. The aim of this study was to investigate the role of WWOX in the regulation of ROS and cell senescence, which is intriguing in terms of the possible mechanism of WWOX contributing to bladder cancer. In this study, we used the AY-27 rat bladder tumor cell line and F344 orthotopic bladder tumor models to reveal the pro-senescence effects of WWOX and the corresponding underlying mechanism in bladder cancer. WWOX-overexpressing lentivirus (LV-WWOX) remarkably stimulated cellular senescence, including increased senescence-associated secretory phenotype (SASP) formation, enlarged cellular morphology, and induced SA-β-Gal-positive staining. A further mechanism study revealed that the pro-senescence effect of LV-WWOX was dependent on increased intercellular reactive oxygen species (ROS) generation, which subsequently triggered p21/p27. Moreover, LV-WWOX significantly inhibited the tumor size by 30.49% in the F344/AY-27 rat orthotopic model (p < 0.05) by activating cellular senescence. The expression of p21 was significantly enhanced in the orthotopic bladder tumors under WWOX treatment. The orthotopic bladder tumors in the groups of rats verified the effect in vivo. Our study suggests that WWOX, an ROS-dependent senescence-induced gene, could be further studied for its therapeutic implications in bladder cancer.

Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration

“…WW2 has one tryptophan, whose function has not been elucidated. However, WW2 may team up with WW1 to maintain an appropriate tertiary conformation that affects the function of WW1 in protein/protein binding [ 42 ]. Nuclear localization of WWOX may occur, especially when cells are stimulated with growth factors or are under apoptotic stress [ 35 ].…”

“…Restoration of the WWOX gene and the resulting protein in cancer cells blocks their growth in vivo and in vitro [ 40 , 41 ]. WWOX protein is not a typical tumor suppressor, as it participates in numerous biological events, including (i) cell survival, proliferation, differentiation, cell cycle regulation, and senescence via complicated signaling pathways [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ], (ii) aging and neurodegeneration [ 22 , 23 , 46 , 47 ], (iii) apoptotic cell death [ 30 , 48 , 49 , 50 , 51 ], (iv) chromosomal DNA stability [ 52 , 53 ], (v) bubbling cell death [ 54 , 55 , 56 ], and (vi) cell-to-cell recognition and migration [ 57 ]. Human newborns lacking the WWOX gene and functional WWOX protein suffer severe neural diseases but do not have spontaneous tumor formation, suggesting WWOX does not fit Knudson’s two-hit hypothesis of tumorigenesis [ 31 , 35 , 45 , 46 ].…”

The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation

“…Nevertheless, in the issue of inducers, we should additionally mention one of the first and most well-characterized mechanisms of cellular senescence, telomere shortening [ 16 ], as well as the first widely used biomarker for the detection of senescent cells, senescence-associated β-galactosidase (SA-β-gal) [ 17 ]. There has been an extensive amount of research, including in the last few years [ 18 , 19 , 20 , 21 ], aimed at investigating the mechanisms of senescence and ways to influence them, using SA-β-gal as a key senescence marker.…”