Resveratrol reverses Doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer
Authors: Yangwei Xu
Qingling Zhang
Jiahui Xu
Huilin Niu
Jian Li
Danli Ye
Deying Liu
Guifang Zhu
Journal: Journal of Experimental & Clinical Cancer Research (2017)
Discipline: CLINICAL MEDICINE
Keywords: Doxorubicin; Drug resistance; EMT; PTEN/Akt; Resveratrol.
Affiliations: Nanfang Hospital/First Clinical Medical School, Southern Medical University, Guangzhou, 510515, China., Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China., Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. ., Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. .

Abstract:  Background: Gastric cancer is one of the major causes of cancer-related mortality worldwide. Most of patients presenting with inoperable gastric cancers rely on systemic chemotherapy for prolongation of survival. Doxorubicin (DOX) is one of the important agents against gastric cancer. Acquired DOX-resistance severely impedes the chemotherapeutic effect, invariably leading to poor prognosis. Resveratrol (RES) as a kind of phytoalexin has demonstrated anti-tumor functions in breast cancer and myeloid leukemia, but its function and mechanism are still unknown in gastric cancer treatment. Methods: CCK8 assay was used to detect the cytotoxicity of DOX and RES to gastric cancer cells. DOX-resistant subclone cell line (SGC7901/DOX) was derived from SGC7901 cells exposed to stepwise increasing concentrations of DOX treatment. We measured the migratory capabilities of SGC7901/DOX cells by Cell scratch test and Transwell assay. SGC7901/DOX cells were treated with DOX, RES, neither or both. Then we analyzed cell survival by CCK8 assay, colony formation by Colony-forming assay, cell apoptosis by Annexin-V-FITC and PI dual staining assay and cell migration by Cell scratch test and Transwell assay. Western blotting was conducted to detect the protein expressions of PTEN/Akt signaling pathway and EMT-related markers. Immunofluorescence was performed to confirm the EMT-related markers expressions. The xenograft model was used to assess the effect of DOX and RES in vivo. The key molecules associated with proliferation, apoptosis and EMT were evaluated by immunohistochemistry in tumor specimens. Results: SGC7901/DOX cells acquired drug resistance and enhancive migratory capability. RES enabled SGC7901/DOX cells to regain DOX sensitivity, mitigated the aggressive biological features, promoted cell apoptosis in vitro and inhibited tumor growth in vivo. Mechanistic studies revealed that SGC7901/DOX cells underwent epithelial-mesenchymal transition (EMT) which was induced by Akt activation, and through activating PTEN, RES inhibited the Akt pathway, and then achieved the reversion of EMT. Conclusion: RES serves as a novel solution to reverse the DOX-resistance of gastric cancer via preventing EMT by modulating PTEN/Akt signaling pathway. DOX-RES combined treatment provides a promising future for gastric cancer patients to postpone drug resistance and prolong survival. 

Retracted: No

PubPeer comments:
 Figure 1i and 5h appear to have some image overlaps. *** ![file] *** ![file] , 
 Dear Dr. Actinopolyspora Biskrensis. Thank you very much for your comments. But the image overlaps weren t belong in this paper. , 
 #2 You are correct, my apologies. , 
 Figure 4D seems to have a repeated image. *** ![file] , 
 #4 Dear Dr. Actinopolyspora Biskrensis, I am the first author, Jiahui Xu. Thanks very much for your concern about our study. After receiving your comments, we immediately checked our primary data and found out that indeed there was duplication in the publication. The primary data was correct and there was clearly difference between the 0 and 24 hour of DOX treated cells. But we accidentally pasted the u201c0 hour u201d image onto the u201c24 houru201d when composing the full figure during the editing process. The primary data was created on 10 11 2015 00:13:42, and only changed on 10 11 2015 00:19:29(See the attached the scan image of our primary data document below ). Although it doesnu2019t affect the results for we focused on the 48-hour migration of cells instead of 24-hour migration, we sincerely apologize for the careless mistake which had not been identified before publication. Again, thank you for your concern and we are going to contact the journal to make an erratum about it.![file] , 
 #3 #4 Thank you for your comments! ,