Correction to: JNK-NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress.

Correction to: Cell Death Dis. 5, e1484 (2014); https://doi.org/10.1038/cddis.2014.408 ; published online 23 October 2014.

JNK-NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress.

Hyperproliferating cancer cells produce energy mainly from aerobic glycolysis, which results in elevated ROS levels. Thus aggressive tumors often possess enhanced anti-oxidant capacity that impedes many current anti-cancer therapies. Additionally, in ROS-compromised cancer cells ubiquitin proteasome system (UPS) is often deregulated for timely removal of oxidized proteins, thus enabling cell survival. Taken that UPS maintains the turnover of factors controlling cell cycle and apoptosis--such as p53 or p73, it represents a promising target for pharmaceutical intervention. Enhancing oxidative insult in already ROS-compromised cancer cells appears as an attractive anti-tumor scenario. TAp73 is a bona fide tumor suppressor that drives the chemosensitivity of some cancers to cisplatin or γ-radiation. It is an important drug target in tumors where p53 is lost or mutated. Here we discovered a novel synergistic mechanism leading to potent p73 activation and cancer cell death by oxidative stress and inhibition of 20S proteasomes. Using a small-molecule inhibitor of 20S proteasome and ROS-inducer--withaferin A (WA), we found that WA-induced ROS activates JNK kinase and stabilizes phase II anti-oxidant response effector NF-E2-related transcription factor (NRF2). This results in activation of Nrf2 target--NQO1 (NADPH quinone oxidoreductase), and TAp73 protein stabilization. The observed effect was ablated by the ROS scavenger--NAC. Concurrently, stress-activated JNK phosphorylates TAp73 at multiple serine and threonine residues, which is crucial to ablate TAp73/MDM2 complex and to promote TAp73 transcriptional function and induction of robust apoptosis. Taken together our data demonstrate that ROS insult in combination with the inhibition of 20S proteasome and TAp73 activation endows synthetic lethality in cancer cells. Thus, our results may enable the establishment of a novel pharmacological strategy to exploit the enhanced sensitivity of tumors to elevated ROS and proteasomal stress to kill advanced tumors by pharmacological activation of TAp73 using molecules like WA.

Secondary metabolites in in vitro cultured plants of the genus Drosera.

Extracts from plantlets of different species of the genus Drosera, grown as in vitro cultures, were evaluated for the level of phenolic secondary metabolites from the group of naphthoquinones and flavonols. The profiles of natural products in the extracts obtained from different species were monitored by HPLC with UV detection at 260 and 330 nm. On the basis of the data obtained, Drosera binata, the species with the highest amount of plumbagin, was selected for further studies. The most effective method of extraction of quinones was established and the composition of phenolic secondary metabolites in the tissues was determined. For the identification of phenolic compounds, HPLC-UV and HPLC-ESI/MS were applied.

[Horizontal osteotomy of the mandibular body with transfer of the inferior dental nerve]. / Ostéotomie horizontale du corps de la mandibule avec transfert du nerf dentaire inférieur.

In a patient with developmental facial asymmetry resulting from unilateral mandibular hyperplasia, irregular height of the mandibular body was strongly manifested on the affected side. Since a large portion of the inferior border of the mandible predicted to be cut off contained almost the whole of the lower alveolar nerve, transfer of the latter was employed. The nerve was surgically isolated along its course, and secured by being lifted while horizontal osteotomy of the mandibular body was performed. The nerve was accommodated in new groove created at a safe distance from the roots of the lower teeth. Postoperative healing was uneventful, but feeling in the region of lower lip was decreased during a few days immediately after surgery. The patient reexamined 18 months later demonstrated satisfactory esthetic and functional result with preserved feeling in the region supplied by the lower alveolar nerve.

[Horizontal osteotomy of the body of the mandible with transfer of the inferior dental nerve]. / Ostéotomie horizontale du corps de la mandibule avec transfert du nerf dentaire inférieur.

By patient with developmental face asymmetry resulting from unilateral mandibular hyperplasia, irregular height of the mandibular body was strongly manifested on affected side. Since a large portion of inferior border of the mandible predicted to be cutted off contained almost the whole of the lower alveolar nerve, transfer of this last was employed. The nerve was surgically isolated along its course, and secured by being lifted while horizontal osteotomy of mandibular body was performed. Next the nerve was accommodated in new groove created in a safe distance from the roots of lower teeth. Postoperative healing was uneventful, but feeling in the region of lower lip was decreased during a few days immediately after surgery. Patient reexamined 18 months later demonstrated satisfactory esthetic and functional result with preserved feeling in the region supplied by the lower alveolar nerve.