Novel insights into the synergistic interaction of a thioredoxin reductase inhibitor and TRAIL: the activation of the ASK1-ERK-Sp1 pathway
Authors: Zhiying Ding
Guimin Luo
Jiacong Shen
Yong Chen
Tingting Lin
Junqiu Liu
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: TRAIL; DTCD; apoptosis; ovarian cancer; DR5
Affiliations: College of Instrumentation and Electrical Engineering, Jilin University, Changchun, PR China. 

Abstract:  Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell death in various types of cancer cells but has little or no effects on normal cells. Unfortunately, not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. Here, we reported that 6-(4-N,N-dimethylaminophenyltelluro)-6-deoxy-β-cyclodextrin (DTCD), a cyclodextrin-derived diorganyl telluride which has been identified as an excellent inhibitor of thioredoxin reductase (TrxR), could sensitize TRAIL resistant human ovarian cancer cells to undergo apoptosis. In vitro, DTCD enhanced TRAIL-induced cytotoxicity in human ovarian cancer cells through up-regulation of DR5. Luciferase analysis and CHIP assays showed that DTCD increased DR5 promoter activity via Sp1 activation. Additionally, DTCD stimulated extracellular signal-regulated kinase (ERK) activation, while the ERK inhibitor PD98059 blocked DTCD-induced DR5 expression and suppressed binding of Sp1 to the DR5 promoter. We further demonstrated that DTCD could induce the release of ASK1 from its complex with Trx-1, and recovered its kinase activity. Meanwhile, suppression of ASK1 by RNA interference led to decreased ERK phosphorylation induced by DTCD. The underlying mechanisms reveal that Trx-1 is heavily oxidized in response to DTCD treatment, in accordance with the fact that DTCD could inhibit the activity of TrxR that reduces oxidized Trx-1. Moreover, using an A2780 xenograft model, DTCD plus TRAIL significantly inhibited the growth of tumor in vivo. Our results suggest that Trx/TrxR system inhibition may play a critical role in apoptosis by combined treatment with DTCD and TRAIL, and raise the possibility that their combination may be a promising strategy for ovarian carcinoma treatment. 

Retracted: Yes

PubPeer comments:
 In this paper, you have mentioned about **simple averaging** of overlapping joint coordinates values to combine data (i.e fuse) of multiple Kinects (v2). Your published data also exhibit monotonically increasing joint coordinate values (fig.B). ![file] But, when I have performed the same experiment with the exact same arrangement of Kinects (v2) (demonstrated in the paper), I am getting quite a different results. I have pointed out the probable cause of that: 1st, each Kinect have its coordinate axis (in both +ve and -ve dimensions). So, while performing simple averaging on overlapping joint coordinates values, actually the computation is performing on a signed number. Hence, after averaging the coordinate value is getting decreased. Monotonically increasing joint coordinate values will not come unless performing any other type of post-processing. Surprisingly, in your published data there are no such negative coordinate values, only positive (monotonically increasing) coordinated values are there. In my experiment I am getting data (after averaging ) like the below figure (L_Ankle_Cor - Left Ankle Coordinates, R_Ankle_Cor - Right Ankle Coordinates): ![file] 2nd, it well known that Kinect joint coordinate value is highly dependent on its view angle. So, while taking data by placing Kinect at 70 degree with the walking path (as mentioned in your paper), it will give biased coordinate values. So, the amplitude of the time series of both ankle will not be same (in both +ve -ve directions) as shown in fig.A. While I am performing the same experiment, getting a signal pattern of both ankle like the below figure: ![file] Data pattern need to come like figure A B to further compute gait parameters. Hence, can you please explain how you have reached to that data pattern. If any other post-processing is required to get that type of data pattern kindly inform it. Thanks. , 
 #1 #1 Thank you for your interest in our paper and my apologies for the late reply. You are right that some kind of pre- or post-processing is needed to combine the data of the Kinect sensors. In the paper it is mentioned that u2018Full-body kinematics was recorded with four spatially and temporally integrated Microsoft Kinect v2 sensors [u2026].u2019 To spatially align the sensors to the same coordinate system, we used a spatial calibration grid before each measurement. The same grid was used to align the coordinate systems of the Optotrak system (the gold standard) with the multi-Kinect set-up. The calibration is also mentioned in other papers on the Interactive Walkway (where the multi-Kinect v2 set-up is used as a motion registration system). Geerse DJ, Roerdink M, Marinus J, van Hilten JJ. Assessing walking adaptability in Parkinsonu2019s disease: u201cThe Interactive Walkwayu201d. Front Neurol. 2018;9:1096 Geerse DJ, Roerdink M, Marinus J, van Hilten JJ. Walking adaptability for targeted fall-risk assessments. Gait Posture. 2019;70:203-210 Hope to have informed you sufficiently. Kind regards, Daphne Geerse ,