Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway
Authors: Venkata Ramesh Dasari
Jasti S Rao
Daniel Fassett
Jeffrey D Klopfenstein
Kiran Kumar Velpula
Kiranpreet Kaur
Meena Gujrati
Dzung H Dinh
Journal: PloS one (2010)
Discipline: Multidisciplinary
Keywords: PTEN; glioblastoma; mesenchymal stem cells; migration; Akt
Affiliations: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA.

Abstract:  Background: PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a tumor suppressor gene implicated in a wide variety of human cancers, including glioblastoma. PTEN is a major negative regulator of the PI3K/Akt signaling pathway. Most human gliomas show high levels of activated Akt, whereas less than half of these tumors carry PTEN mutations or homozygous deletions. The unique ability of mesenchymal stem cells to track down tumor cells makes them as potential therapeutic agents. Based on this capability, new therapeutic approaches have been developed using mesenchymal stem cells to cure glioblastoma. However, molecular mechanisms of interactions between glioma cells and stem cells are still unknown. Methodology/principal findings: In order to study the mechanisms by which migration of glioma cells can be inhibited by the upregulation of the PTEN gene, we studied two glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310) alone and in co-culture with human umbilical cord blood-derived mesenchymal stem cells (hUCBSC). Co-cultures of glioma cells showed increased expression of PTEN as evaluated by immunofluorescence and immunoblotting assays. Upregulation of PTEN gene is correlated with the downregulation of many genes including Akt, JUN, MAPK14, PDK2, PI3K, PTK2, RAS and RAF1 as revealed by cDNA microarray analysis. These results have been confirmed by reverse-transcription based PCR analysis of PTEN and Akt genes. Upregulation of PTEN resulted in the inhibition of migration capability of glioma cells under in vitro conditions. Also, wound healing capability of glioma cells was significantly inhibited in co-culture with hUCBSC. Under in vivo conditions, intracranial tumor growth was inhibited by hUCBSC in nude mice. Further, hUCBSC upregulated PTEN and decreased the levels of XIAP and Akt, which are responsible for the inhibition of tumor growth in the mouse brain. Conclusions/significance: Our studies indicated that upregulation of PTEN by hUCBSC in glioma cells and in the nude mice tumors downregulated Akt and PI3K signaling pathway molecules. This resulted in the inhibition of migration as well as wound healing property of the glioma cells. Taken together, our results suggest hUCBSC as a therapeutic agent in treating malignant gliomas. 

Retracted: Yes

PubPeer comments:
 Figure 1B. * In green: The left PTEN panel looks similar to the right PTEN panel (not sure, but worth mentioning) * In blue: The left pAktSer473 panel looks similar to the right panel ![file] , 
 Figures 1C and 1E. * In turquoise: The first 5 lanes of the Actin panel in Figure 1C look remarkably similar to the Actin panel in Figure 1E. The lanes represent different experiments. Note small protrusions in the bottom part of the bands visible in lanes 3 and 4, and a protrusion in the top part of the band visible in lane 5. ![file] , 
 Figure 2C and 5AB. * In purple: The left GAPDH panel in Figure 2C looks remarkably similar to the GAPDH panels of Figure 5A and B. The latter 2 represent the same set of samples, but the panel in Figure 2C does not. ![file] , 
 Figure 5C. * In red: The XIAP panel looks unexpectedly similar to the PDGFR panel. Two little white dots are shown with arrows. ![file] , 
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0231283 After this article [1] was published, concerns were raised about results reported in Figures 1, 2, and 5. Specifically: PTEN and pAktSer473 blots appear the same in the left and right panels of Figure 1B, where the data are reported as representing different experiments. u03b2-actin data look similar in lanes 1u20135 of Figure 1C and in Figure 1E; the data are reported as representing different experiments. GAPDH panels appear similar in Figure 2C (left panel), Figure 5A, and Figure 5B. Figures 5A and 5B represent the same experimental conditions but Figure 2C represents a different experiment. XIAP and PDGFR panels appear similar in Figure 5C. The first author provided electronic image data that are available to support the figures mentioned above, but these data did not clarify the issues outlined. In addition, the article reports a cDNA microarray experiment but does not mention deposition of the microarray data in a public repository as required by the PLOS Data Policy that was in effect when the article was submitted. The above concerns call into question the reliability of the reported results and whether the article complied with the journalu2019s editorial policies. In light of these issues, the PLOS ONE Editors retract this article. VRD did not agree with retraction. The other authors either could not be reached or did not respond directly. Reference 1.Dasari VR, Kaur K, Velpula KK, Gujrati M, Fassett D, Klopfenstein JD, et al. (2010) Upregulation of PTEN in Glioma Cells by Cord Blood Mesenchymal Stem Cells Inhibits Migration via Downregulation of the PI3K Akt Pathway. PLoS ONE 5(4): e10350. https: doi.org 10.1371 journal.pone.0010350 , 
 https: retractionwatch.com 2020 04 06 former-star-cancer-researcher-who-sued-his-university-for-discrimination-notches-eighth-retraction ,