The Oxidation States of DJ-1 Dictate the Cell Fate in Response to Oxidative Stress Triggered by 4-HPR: Autophagy or Apoptosis?

Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and they highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease. Cancer Res; 75(22); 4839-51. Ó2015 AACR.

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“…Western blotting, real-time PCR, and immunoprecipitation were performed as described (20), with details in Supplementary information.…”

Section: Western Blotting Real-time Pcr and Immunoprecipitationmentioning

confidence: 99%

“…Tumor processing and immunofluorescence assays were performed as described previously (20), with details provided in the Supplementary information.…”

Section: Ihc and Immunofluorescence Assaymentioning

confidence: 99%

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

et al. 2015

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“…JNK and p38 MAPK are activated by a wide range of cellular stresses including ROS. Recent findings in Hela cells have now implicated DJ-1, a multifunctional oxidative stress response protein and the ASK-1-p38 MAPK pathway to regulate the balance between autophagy and apoptosis depending on the relative concentration of FEN and subsequent level of ROS generation [22]. ASK1-mediated activation of JNK and p38 were found to be responsible for the FEN-induced autophagy or apoptosis, respectively.…”

Section: Ros Dj-1 Ask1 P38 Apoptosis Pathwaymentioning

confidence: 98%

“…FEN induces apoptosis in cells that are resistant to RA, suggesting that FEN-induced apoptosis may involve RAR-independent mechanism(s), such as increased generation of reactive oxygen species (ROS) and ceramide species and activation of stress kinases, endoplasmic reticulum (ER) stress and autophagy pathways [21]. However, high concentrations of FEN are required to induce apoptosis [22,23]. With this in mind, high doses of FEN and formulation within novel lipid matrices to improve FEN bioavailability and to attain higher plasma concentrations have been tested in adults and in children with neuroblastoma [24,25].…”

Section: Cancer Chemoprevention Trialsmentioning

confidence: 99%

The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes

Mody

Mcilroy

2014

Biochemical Pharmacology

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Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its clinical use remains a genuine possibility due to a favourable toxicological profile and accumulation in fatty tissues. Like other well-characterised pharmacological therapies, Fenretinide has been shown to affect multiple signalling pathways. Recent findings have discovered additional beneficial properties the synthetic retinoid was not intentionally designed for, including the prevention of high-fat diet-induced obesity and insulin resistance. These preclinical findings in rodents are timely since obesity has reached pandemic proportions and safe effective therapeutics are severely lacking. Recent investigations have proposed various mechanisms of action for the beneficial effects of Fenretinide. This review covers the current knowledge about Fenretinide's use as a therapy for cancer and potential to treat obesity, insulin resistance and glucose intolerance. An overview of the signalling pathways manipulated by Fenretinide including retinoid homeostasis, reactive oxygen species generation and inhibition of ceramide synthesis will be presented and insights into apoptosis and/or autophagy induction by Fenretinide will also be discussed. The largely unexplored area of Fenretinide metabolites as alternative therapeutic options and how these may be relevant will also be presented. Fenretinide shows great promise, but unfortunately evidence is lacking from clinical trials on Fenretinide's effectiveness in humans. Finally we identify what action can be taken to further progress the investigation of this extremely important retinoid.

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“…Among the two interactants of SG2NA, Akt has long been accepted as a nodal player in cancer cell survival [33], but the role of DJ-1 in cancer development has lately been appreciated. Available data suggest that DJ-1 is involved in multiple facets of cancer development i.e., maintenance of transformed phenotype, regulation of cell growth, survival, metastasis and resistance to chemotherapeutics [18,22,34,35]. Such wider role of DJ-1 is likely due to its diverse functions including RNA-binding, redox-regulated chaperone activity, scavenging of ROS, cysteine proteolysis and transcriptional coactivation [34,36,37].…”

Section: Discussionmentioning

confidence: 99%