Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential
Authors: D Iliopoulos
K A McCorkell
Y Pekarsky
T Druck
H Ishii
M Fabbri
F Trapasso
C M Croce
S Semba
S Volinia
L D Barnes
K Huebner
P N Garrison
Journal: Oncogene (2006)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Fhit tumor suppressor; diadenosine polyphosphates; proapoptotic effector; cancer cells; adenoviruses
Affiliations: Comprehensive Cancer Center and Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, 43210, USA.

Abstract:  The Fhit tumor suppressor binds and hydrolyses diadenosine polyphosphates and the Fhit-substrate complex has been proposed as a proapoptotic effector, as determined by infection of susceptible cancer cells with adenoviruses carrying wild-type fragile histidine triad (FHIT) or catalytic site mutants. The highly conserved Fhit tyrosine 114 (Y114), within the unstructured loop C-terminal of the catalytic site, can be phosphorylated by Src family tyrosine kinases, although endogenous phospho-Fhit is rarely detected. To explore the importance of Y114 and identify Fhit-mediated signaling events, wild-type and Y114 mutant FHIT-expressing adenoviruses were introduced into two human lung cancer cell lines. Caspase-dependent apoptosis was effectively induced only by wild-type but not Y114 mutant Fhit proteins. By expression profiling of FHIT versus mutant FHIT-infected cells, we found that survivin, an Inhibitor of Apoptosis Protein (IAP) family member, was significantly decreased by wild-type Fhit. In addition, Fhit inhibited activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway; loss of endogenous Fhit expression caused increased Akt activity in vitro and in vivo, and overexpression of constitutively active Akt inhibited Fhit-induced apoptosis. The results indicate that the Fhit Y114 residue plays a critical role in Fhit-induced apoptosis, occurring through inactivation of the PI3K-Akt-survivin signal pathway. 

Retracted: No

PubPeer comments:
 Figure 7 in this article is fabricated. The same four images have been used in another JBUON paper (DOI: 32521875) in the same issue. When comparing the two articles, none of the authors are common and the institutions are different. They origin from the same Chinese province though. Together with the strange email addresses, I think these articles have been fabricated by some Chinese papermill. ![file] , 
 #1 Even without the double publication, internal repetitions within the fourth panel cause concern. ![file] , 
 I note as an afterthought that the Fig 7 addressed in comment #2, with its internally-repetitive 4th panel, is **not** the Fig 7 addressed in comment #1. The paper appears to have been revised or corrected, replacing the figure in question, with the version currently available at the journal website originating on 23 December 2020. ![file] The original figures are still available, with archived copies at [SemanticScholar] . -------------------------------------------------------------------------------------------------------- There are other problems so another revision may be in order. *[right]* Figure 3 from [Shi et al (2020)] .  Effect of Juglone on the percentage of the apoptotic OVCAR-3 cells as depicted by annexin V PI staining . *[left]* Figure 3 from [Ouyang Xu (2019)] .  Annexin V PI staining showing the effect of Sweroside on the percentage of the apoptotic of U251 cells. With increasing sweroside dose the percentage of apoptotic cells increased significantly . ![file] Erased areas in the corner of each quadrant in the 2020 versions suggest that the original quadrant percentages have been effaced and replaced. , 
 The paper has reverted to its original version, and acquired a [May June Expression of Concern] .  Following the publication of this article [1], readers drew to our attention that part of the data was possibly unreliable. We sent emails to the authors with a request to provide the raw data to prove the originality, but received no reply. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause. , 
 Retracted [November December 2021] .  Following the publication of this article [1], readers drew to our attention that part of the data was unreliable: Figures of this article appeared in other articles (by totally different authors). The authors were requested to provide the raw data and were also asked for an explanation to account for these concerns, however, the Editorial Office hasnu2019t received any reasonable reply. To make the readers alert, we published an Expression of Concern for this article months ago. Now we completed the investigation and decided to retract this article. Authors were informed of the retraction. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause. ,