Oncolytic adenovirus‑mediated mda‑7/IL‑24 expression suppresses osteosarcoma growth and enhances sensitivity to doxorubicin
Authors: Zongming Liu
Dongxu Zhao
Xiaona Zhang
Libo Xu
Hongping Yuan
Yang Zhang
Journal: Molecular Medicine Reports (2015)
Discipline: CLINICAL MEDICINE
Keywords: Osteosarcoma; Melanoma differentiation associated gene‑7 (Mda7); Interleukin (IL)‑24; Oncolytic adenovirus; Cell viability
Affiliations: Department of Anesthesiology, Jilin Cancer Hospital, Changchun, Jilin 130000, P.R. China., Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130033, P.R. China., Department of Nephrology, The Fourth Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, P.R. China., Department of Neurosurgery, The First Affiliated Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, P.R. China., Department of Anesthesiology, The First Affiliated Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, P.R. China., Department of Orthopedics, China‑Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, P.R. China.

Abstract:  Osteosarcoma (OS) is a malignant disease with a high mortality rate and poor response to current chemotherapy. Melanoma differentiation associated gene‑7 (Mda7)/interleukin (IL)‑24 has been demonstrated to suppress the growth of OS. However, the expression level of Mda7/IL‑24 mediated by the current adenoviral vector is limited for effective clinical treatment of OS. In order to solve this issue, an oncolytic adenovirus was employed to express IL‑24 (OA‑IL‑24) in OS cells. Quantitative polymerase chain reaction, immunoblot and ELISA assays verified that OA‑IL‑24 expressed IL‑24 at a higher level than the replication‑deficient adenoviral vector, Ad‑IL24. OA‑IL‑24 infection led to decreased cell viability and increased apoptosis of OS cells, compared with Ad‑IL‑24. Animal studies further confirmed the increased anti‑tumor activity of OA‑IL‑24. Notably, OA‑IL‑24 was also found to sensitize OS cells to doxorubicin. OA‑IL‑24‑induced multiple drug resistance reversion was associated with reduced expression of Pgp and BCRP1, as well as minimized autophagy. Furthermore, restoring Pgp and BCRP1 expression as well as autophagy, was able to rescue the effect of IL‑24 on the cytotoxicity of doxorubicin to OS. In conclusion, a method for inducing a high expression of IL‑24 in OS was provided. In addition, IL‑24 was demonstrated to increase the sensitivity of OS to doxorubicin. 

Retracted: Yes

PubPeer comments:
 Fig 6.  (A) OA-IL-24 (10 MOI) was added to U2OS cells together with pcDNA3.1-EGFP or pcDNA3.1-Pgp plus pcDNA3.1-BCRP1. After 48 h treatment, total proteins were isolated for immunoblot analysis of Pgp and BCRP1.... (C) U2OS cells were treated with OA-IL-24 (10 MOI) and or chloroquine (25 mM). After 48 h treatment, total proteins were isolated for immunoblot analysis of LC3-I and LC3-II ![file] Boxes are to facilitate comparison with Fig 6b from [Hong et al (2015)] .  Western blot assay was conducted to confirm the above results. ![file] *[left]* Fig 5a from [Peng et al (2016)] .  A549 and H460 cells were infected with AdpiR-55490 or Ad-EGFP (10 MOI), and 48 h later, immunoblot assay was performed to detect expression level of phosphorylated mTOR . *[right]* Fig 2a from [Song et al (2016)] .  MEF2D and Ki67 expressions were detected by immunoblotting 48 h after A549 and H460 cells were transfected with siMEF2D (50 nM) or control siRNA (50 nM) . ![file] , 
 Fig 3C.  The expression of ... apoptosis were evaluated by immunohistological staining in tumor sections .  The expression of apoptosis is unclear; perhaps some details were omitted. Two panels are the same. ![file] , 
 Figs 1B, 5A.  U2OS and a primary OS cell were infected with Ad-EGFP, OA-EGFP, Ad-IL-24 or OA-IL-24 (10 MOI) for 48 h. Immunoblot assays were performed to detect the expression level of IL-24 ;  U2OS and primary OS cells were infected with Ad-EGFP, OA-EGFP, Ad-IL-24 or OA-IL-24 (10 MOI) for 48 h. Immunoblot assays were performed to detect the expression level of Pgp, BCRP1 and MRP1 . ![file] Figs 1C, 6A from [Wan et al (2016)] .  Northern blotting was performed to confirm the expression profile of miR-155 ;  immunoblot assays were performed to detect the protein expression levels of HBP1 . ![file] Unexpected similarities. , 
 #1 Fig 6A again, with more colored boxes: ![file] Figs 5F,G from [Song et al (2016)] .  Immunoblot analysis was performed to examine the expression of MEF2D proteins under the above treatment. ![file] Tubulin or GAPDH? , 
 Retracted [4 October 2021] .  Following the publication of this paper, it was drawn to the Editorsu2019 attention by a concerned reader that the western blot assay data shown in Figs. 1B, 5A, 6A and C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to *Molecular Medicine Reports*, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. ,